What is the central question of this study? Protease-activated receptor 2 (PAR2) is located in the endothelial cells of skin vessels and eccrine sweat glands. However, a functional role of PAR2 in the control of cutaneous blood flow and sweating remains to be assessed in humans in vivo. What is the main finding and its importance? Our results demonstrate that in normothermic resting humans in vivo, activation of PAR2 elicits cutaneous vasodilatation partly through nitric oxide synthase-dependent mechanisms, but does not mediate sweating. These results provide important new insights into the physiological significance of PAR2 in human skin. Protease-activated receptor 2 (PAR2) is present in human skin, including keratinocytes, endothelial cells of skin microvessels and eccrine sweat glands. However, whether PAR2 contributes functionally to the regulation of cutaneous blood flow and sweating remains entirely unclear in humans in vivo. We hypothesized that activation of PAR2 directly stimulates cutaneous vasodilatation and sweating via actions of nitric oxide synthase (NOS) and cyclo-oxygenase (COX). In 12 physically active young men (29 ± 5 years old), cutaneous vascular conductance (CVC) and sweat rate were measured at four intradermal microdialysis forearm skin sites that were treated with the following: (i) lactated Ringer's solution (control); (ii) 10 mm N -nitro-l-arginine (NOS inhibitor); (iii) 10 mm ketorolac (COX inhibitor); or (iv) a combination of both inhibitors. At all sites, a PAR2 agonist (SLIGKV-NH ) was co-administered in a dose-dependent fashion (0.06, 0.18, 0.55, 1.66 and 5 mm, each for 25 min). The highest dose of SLIGKV-NH (5 mm) increased CVC from baseline at the control site (P ≤ 0.05). This increase in CVC associated with PAR2 activation was attenuated by NOS inhibition regardless of the presence or absence of simultaneous COX inhibition (both P ≤ 0.05). However, COX inhibition alone did not affect the PAR2-mediated increase in CVC (P > 0.05). No increase in sweat rate was measured at any administered dose of SLIGKV-NH (all P > 0.05). We show that in normothermic resting humans in vivo, PAR2 activation does not increase sweat rate, whereas it does modulate cutaneous vasodilatation through NOS-dependent mechanisms.

Protease‐activated receptor 2 (PAR‐2) is a G protein‐coupled receptor stimulated by the enzyme trypsin and is responsible for modulating the inflammatory response. It has been localized ‐on both the eccrine sweat glands and cutaneous vascular endothelial cells. In particular, activation of PAR‐2 contributes to the degranulation of secretory cells in the eccrine sweat glands and may therefore play a role in modulating the sweating response in humans. However, it is unknown if activation of PAR‐2 augments cutaneous vasodilation and sweating during exercise in the heat. Therefore, the purpose of the present study was to investigate these heat loss responses in young adults exercising in the heat. Five healthy, habitually active, young males (25 ± 6 years) performed 50‐min of moderate intensity (~55% VO2peak) cycling in the heat (35°C, 20% relative humidity) followed by a 30‐min recovery period. Local forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC, laser‐Doppler perfusion units/mean arterial pressure) were recorded at four skin sites, continuously perfused with: 1) Lactated Ringer's (Control), 2) 0.05 mM, 3) 0.5 mM, or 4) 5 mM SLIGKV‐NH2 (PAR‐2 agonist) via intradermal microdialysis. There were two baseline measurements conducted at different ambient temperatures. The first baseline (Baseline 1) was measured at 25°C, 20% relative humidity and the second baseline (Baseline 2) depicted the onset of heat stress and was measured at 35°C, 20% relative humidity. During Baseline 1, there was a tendency for an increase in CVC at both the 0.5 mM (14 ± 3% CVCmax, P = 0.078) and 5 mM (21 ± 7% CVCmax, P = 0.067) SLIGKV‐NH2 site relative to Control. At the end of the 50‐min exercise bout, there were no significant differences in CVC between all sites (Control: 71 ± 4% CVCmax; 0.05 mM: 69 ± 8% CVC max; 0.5 mM: 68 ± 5% CVCmax; 5 mM: 74 ± 9% CVCmax; P > 0.05) Further, we also show that activation of PAR‐2 at all concentrations of SLIGKV‐NH2 did not elicit significant changes in sweat rate at the end of exercise (Control: 1.31 ± 0.24; 0.05 mM: 1.52 ± 0.21; 0.5 mM: 1.55 ± 0.12; 5 mM: 1.51 ± 0.13 mg·min−1·cm−2; P > 0.05). In summary, our preliminary findings demonstrate that PAR‐2 activation exhibits a tendency to increase CVC at higher concentrations (0.5 and 5 mM) of SLIGKV‐NH2 relative to Control during baseline conditions. However, this increase is not present at the onset of and during heat stress, thereby indicating that PAR‐2 does not contribute to the modulation of sweating and cutaneous vasodilation during moderate intensity exercise in the heat.Support or Funding InformationThis 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).

Protease-activated receptor 2 (PAR2) exists in the endothelial cells of skin vessels and eccrine sweat glands. We evaluated the hypothesis that exogeneous activation of PAR2 augments cutaneous vasodilatation and sweating during rest and exercise in the heat. In 10 young males (23 ± 5 y), cutaneous vascular conductance (CVC) and sweat rate were measured at four forearm skin sites treated with either 1) lactated Ringer (Control), 2) 0.05 mM, 3) 0.5 mM, or 4) 5 mM SLIGKV-NH 2 (PAR2 agonist). Participants initially rested in a semi-recumbent posture under a normothermic ambient condition (25°C) for~60 min. Thereafter, ambient temperature was increased to 35°C while the participants rested for an additional 60 min. Participants then performed a 50-min bout of cycling (~55% of their predetermined peak oxygen uptake) followed by a 30-min recovery period. Administration of 5 mM SLIGKV-NH 2 increased cutaneous vascular conductance relative to the Control site during normothermic resting (P ≤ 0.05). However, we showed that relative to the Control site, no effect on CVC was observed for any administered dose of SLIGKV-NH 2 (0.05-5 mM) during rest (33-39%max CVC), end-exercise (68-70%max CVC), and postexercise recovery (49-53%max CVC) in the heat (all P > 0.05). There were no differences in sweat rate between the Control and all SLIGKV-NH 2-treated sites throughout the protocol (0.21-0.23, 1.20-1.27, and 0.32-0.33 mg•min −1 •cm −2 for rest, end-exercise, and postexercise in the heat, respectively, all P > 0.05). We show that while exogeneous PAR2 activation induces cutaneous vasodilatation during normothermic rest, it does not influence the cutaneous blood flow and sweating responses during rest, exercise or recovery in the heat.