Activation of Protease‐Activated Receptor 2 Directly Mediates Cutaneous Vasodilatation but Not Sweating in Humans In Vivo: Roles of Nitric Oxide Synthase and Cyclooxygenase
Bibliographic record
Abstract
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).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".