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Activation of Protease‐Activated Receptor 2 Directly Mediates Cutaneous Vasodilatation but Not Sweating in Humans In Vivo: Roles of Nitric Oxide Synthase and Cyclooxygenase
Author(s) -
McNeely Brendan Douglas,
Fujii Naoto,
Zhang Sarah Y.,
Daquan Mercy O.,
Kenny Glen P.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.840.7
Subject(s) - microdialysis , vasodilation , nitric oxide , nitric oxide synthase , cyclooxygenase , agonist , chemistry , reactive hyperemia , in vivo , medicine , ketorolac , endocrinology , pharmacology , anesthesia , receptor , enzyme , biology , biochemistry , microbiology and biotechnology , analgesic , central nervous system
Protease‐activated receptor 2 (PAR2) is present in the endothelial cells of skin microvessels and eccrine sweat glands in humans. Notably, this receptor has been shown to play a role in the vascular control of larger arteries and the control of epidermal permeability. However, it remains unclear if PAR2 functionally contributes to the regulation of cutaneous blood flow and sweating in humans. Therefore, the objective of the current study was to determine whether the activation of PAR2 directly stimulates cutaneous vasodilation and sweating through nitric oxide synthase (NOS) and cyclooxygenase (COX) mediated mechanisms. In twelve young males (29±5 years), cutaneous vascular conductance (CVC, measured via laser‐Doppler perfusion units/mean arterial pressure) and sweat rate (measured via ventilated capsule) were evaluated at four intradermal microdialysis forearm skin sites that were constantly perfused with either 1) lactated Ringer (Control), 2) 10 mM N ω ‐nitro‐L‐arginine (NOS inhibitor), 3) 10 mM ketorolac (COX inhibitor), or 4) a combination of 10 mM N ω ‐nitro‐L‐arginine + 10 mM ketorolac. The PAR2 agonist (SLIGKV‐NH 2 ) was co‐administered at all sites in a dose‐dependent fashion (0.06, 0.18, 0.55, 1.66, and 5 mM, each for 25 min). Throughout the protocol, participants rested in a semi‐recumbent position in a thermoneutral room (23°C). Responses were compared at baseline and the last 5 min of each dose administered. The highest dose of SLIGKV‐NH 2 (5 mM) increased CVC from baseline (BL) at the Control site (BL: 15 ± 8% CVC max , 5 mM: 37 ± 22% CVC max ; P ≤ 0.01). This increase in CVC associated with PAR2 activation was attenuated by NOS inhibition with or without simultaneous COX inhibition (Control: 37 ± 22%CVC max , NOS inhibition: 25 ± 16% CVC max , NOS+COX inhibition: 23 ± 16% CVC max ; both P ≤ 0.05). However, COX inhibition alone had no effect on the PAR2 mediated increase in CVC at all doses (all P > 0.05). No increase in sweat rate was measured at any administered dose of SLIGKV‐NH 2 irrespective of the agent co‐administered (all P > 0.05). In conclusion, we show that in normothermic resting humans, in vivo activation of PAR2 directly mediates cutaneous vasodilation through NOS‐dependent mechanisms without any contribution of COX mediated pathways. Alternatively, the same activation of PAR2 does not lead to increases in forearm sweat rate. Support or Funding Information This study was supported by the Natural Sciences and Engineering Research Council of Canada (Discovery grant, RGPIN‐06313‐2014; Discovery Grants Program ‐ Accelerator Supplement, RGPAS‐462252‐2014; funds held by Dr. Glen P. Kenny).