Activation of protease‐activated receptor 2 mediates cutaneous vasodilatation but not sweating: roles of nitric oxide synthase and cyclo‐oxygenase

Abstract

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.

Assessment of the Effect of 3% Diclofenac Sodium on Photodamaged Skin by Means of Reflectance Confocal Microscopy

“…It is also known that keratinocytes release prostaglandins (PG) through PAR-2 (protease-activated receptor 2), promoting melanocyte dendricity and transfer of melanosomes to keratinocytes (25). COX has also been implicated in the PAR-2 pathway (26). We hypothesise that COX inhibition of DSHA (24) over keratinocytes would reduce PG release mediated through PAR-2, thus decreasing PG-induced melanocyte dendricity and, consequently, reducing transfer of melanin to keratinocytes, which would decrease mottled pigmentation in RCM exploration corresponding to a decreased pigmentation of epidermal keratinocytes.…”

The effect of exogenous activation of protease-activated receptor 2 on cutaneous vasodilatation and sweating in young males during rest and exercise in the heat

“…Direct evaluation of this possibility is required, as previous studies have demonstrated that substances which can cause cutaneous vasodilatation under normothermic resting conditions do not necessarily lead to cutaneous vasodilatation during wholebody heat stress or local heating [14,15]. While we observed an influence of the PAR2 agonist on cutaneous vasodilatation during normothermic resting, there was no effect of PAR2 activation on sweating during normothermic rest [13]. However, the lack of an effect is not surprising given that the modulation of the sweating may only occur when the sweat gland is pre-activated [16].…”

“…Thereafter, the fibres were continuously perfused in a counterbalanced manner with: 1) lactated Ringer solution (Control) 2) 0.05 mM, 3) 0.5 mM, or 4) 5 mM of the PAR2 agonist, SLIGKV-NH 2 (Alomone labs, Jerusalem, Israel). The concentrations of SLIGKV-NH 2 were selected based on our previous work [13]. The agents were perfused through the fibre at a rate of 4 μL•min −1 via a microinfusion pump (Model 400, CMA Microdialysis, Solna, Sweden) for at least 60 min to ensure PAR2 receptor activation with SLIGKV-NH 2 .…”

“…We recently reported that PAR2 agonist administration caused cutaneous vasodilatation under normothermic resting conditions [13]. However, it remains to be determined if a similar response would be observed during heat stress wherein cutaneous vasodilatation plays an important role in the transfer and dissipation of heat.…”

“…To the best of our knowledge, there are no antagonists of PAR2 that are known to be safe for in vivo human study. However, one agonist SLIGKV-NH 2 , can be safely administered to humans [7,13]. Assessing how this PAR2 agonist modulates cutaneous vasodilatation and sweating would provide important insights into how PAR2 may functionally mediate the regulation of these heat loss responses of cutaneous vasodilatation and sweating such as during a heat stress.…”