Objectives Heat shock protein 90 (HSP90) contributes to cutaneous vasodilatation during exercise in the heat through nitric oxide (NO) synthase (NOS)–dependent mechanisms in young adults. We hypothesized that similar responses would be observed in older middle‐aged adults. Methods In nineteen habitually active older middle‐aged (56 ± 5 years) men (n = 9) and women (n = 10), cutaneous vascular conductance (CVC) was measured at four forearm skin sites continuously treated with (a) lactated Ringers solution (Control), (b) 10 mmol/L L‐NAME (NOS inhibitor), (c) 178 μmol/L geldanamycin (HSP90 inhibitor), or (d) 10 mmol/L L‐NAME and 178 μmol/L geldanamycin combined. Participants rested in an upright semi‐recumbent position in the heat (35°C) for 70 minutes, followed by a 50‐minute bout of moderate‐intensity cycling (~55% peak oxygen uptake) and a 30‐minute recovery period in the heat. Results In both men and women, we observed no significant effects of HSP90 inhibition on CVC throughout rest, exercise, and recovery in the heat (all P > 0.27). Conversely, NOS inhibition and dual NOS and HSP90 inhibition attenuated CVC relative to Control throughout the protocol (all P ≤ 0.05). Conclusions While NOS mediates cutaneous vasodilatation during rest, exercise, and recovery in the heat, HSP90 does not measurably influence this response in habitually active older middle‐aged men or women under these conditions.

<b><i>Background:</i></b> Protease-activated receptor 2 (PAR2) exists in the cutaneous vasculature and eccrine sweat glands. We previously showed that in young habitually active men, exogenous PAR2 activation via the agonist SLIGKV-NH₂ had no effect on heat loss responses of cutaneous vasodilatation and sweating during rest or exercise in the heat. However, ageing is associated with altered mechanisms governing these responses. Thus, the effect of exogenous PAR2 activation on cutaneous vasodilatation and sweating in older individuals may differ from that in young adults. <b><i>Methods:</i></b> Local cutaneous vascular conductance (CVC) and sweat rate were measured in 9 older males (62 ± 4 years) at four forearm skin sites treated with the following: (1) lactated Ringer solution (control), (2) 0.05 mM, (3) 0.5 mM, or (4) 5 mM SLIGKV-NH₂. Measurements were performed while participants rested in a non-heat-stress environment (25°C) for ∼60 min and an additional 50 min thereafter in the heat (40°C). Participants then performed 50 min of cycling at a fixed metabolic heat load of 200 W/m² (to maintain the same thermal drive for heat loss between participants) followed by a 30-min recovery. <b><i>Results:</i></b> CVC during non-heat-stress resting was elevated from the control site with 5 mM SLIGKV-NH₂ (<i>p</i> ≤ 0.05), but this response was not observed during ambient heat exposure. By contrast, 5 mM SLIGKV-NH₂ lowered CVC during the early stage (10 and 20 min) of exercise compared to the control site (all <i>p</i> ≤ 0.05). Although sweating during non-heat-stressed and heat-stressed resting was not affected by any dose of SLIGKV-NH₂, it was reduced with all SLIGKV-NH₂ doses relative to the control site during and following exercise (all <i>p</i> ≤ 0.05). <b><i>Conclusion:</i></b> We show that while exogenous PAR2 activation induces cutaneous vasodilatation at rest under non-heat-stressed conditions, it attenuates cutaneous vasodilatation and sweating during and following an exercise-induced heat stress in older men.

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Stimulation of protease‐activated receptor 2 (PAR‐2), which is present on cutaneous epithelial cells and eccrine sweat glands, induces cutaneous vasodilation but not sweating in young adults during passive rest in a thermoneutral environment (~23°C). While recent data from our laboratory suggest that PAR‐2 activation does not influence these heat loss responses in young males during rest or exercise in a hot environment, it is unknown how stimulation of this receptor modulates cutaneous vasodilation and sweating in older males. Ten healthy older males (age: 61 ± 4 yrs) rested in a thermal chamber regulated to 25°C (baseline) while four microdialysis fibres were continuously perfused with 1) lactated Ringer's (Control) or the PAR‐2 receptor agonist SLIGKV‐NH2 at concentrations of 2) 0.05 mM, 3) 0.5 mM and 4) 5 mM. Chamber temperature was then increased to 40°C and, following ~60 min of passive heat exposure, participants performed 50‐min of moderate intensity cycling (200 W·m−2 of metabolic heat production). Local forearm cutaneous vascular conductance (CVC) and sweat rate were measured continuously at each treatment site. At baseline, CVC was elevated at the 5 mM SLIGKV‐NH2 skin site (40 ± 15%CVCmax) relative to Control (11 ± 4%CVCmax; P<0.01). By contrast, no differences were observed between treatment sites during passive exposure to 40°C (all P≥0.08) or at end‐exercise (all P≥0.22). Sweat rate was similar between treatment sites during both the baseline (all P≥0.53) and passive heat exposure (P≥0.28) periods. However, end‐exercise sweat rate was attenuated compared to Control (1.62 ± 0.30 mg·min−1·cm−2) with 0.05 mM (1.20 ± 0.29 mg·min−1·cm−2; P<0.01), 0.5 mM (1.12 ± 0.24 mg·min−1·cm−2; P<0.01) and 5 mM (1.15 ± 0.26 mg·min−1·cm−2; P=0.01) doses of SLIGKV‐NH2. These findings indicate that while PAR‐2 activation can cause cutaneous vasodilation during rest in thermoneutral conditions, its influence is diminished during both passive exposure and exercise in a hot environment. Further, in contrast to previous observations made in young adults, PAR‐2 activation diminished the sweating response in older males during exercise in the heat.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Heat Shock Protein 90 (HSP90) is involved in numerous cellular enzymatic processes and it is up‐regulated during exercise in the heat in a variety of cell types. In vitro and in vivo evidence indicates that HSP90 directly enhances nitric oxide (NO) bioavailability via binding to and stabilization of NO synthase. In young males, we previously demonstrated a role for HSP90 in mediating cutaneous vasodilation, but not sweating, during exercise in the heat and this effect was determined to be NO‐dependent. Healthy ageing attenuates both cutaneous vasodilation and sweating responses during exercise in the heat, in part, due to reduced NO bioavailability. However, the contribution of HSP90 in mediating these heat loss responses in older adults remains poorly understood. Thus, the purpose of this study was to evaluate the contribution of HSP90 in modulating sweating and cutaneous vasodilation in healthy habitually active older adults exercising in the heat and to determine whether this contribution acts through the NO pathway. Eleven (M=8; F=3) healthy older adults (55 ± 5 years) exercised for 50 min at 55% VO2peak in the heat (35°C, 30% relative humidity). Cutaneous vascular conductance (CVC, measured via laser Doppler flowmetry) and sweating (measured via ventilated capsules) were measured at four forearm skin sites receiving either: 1) Lactated Ringer's solution (Control), 2) 10 mM NG‐nitro‐L‐arginine methyl ester (L‐NAME, a specific NO synthase inhibitor), 3) 178 mM Geldanamycin (Gelda, an HSP90 inhibitor), or 4) a combination of 10 mM L‐NAME +178 mM Gelda (L+G), via intradermal microdialysis. A 5% DMSO solution was used to fully dissolve Gelda, and was also added to the other sites for consistency. At the end of exercise, CVC was not different between Gelda (68 ± 18% CVCmax) and Control (65 ± 12% CVCmax; all P < 0.05) sites. However, CVC was reduced at L‐NAME (52 ± 20% CVCmax) and L+G (52 ± 17% CVCmax) sites, relative to both Control and Gelda sites (all P<0.05). Sweat rates were lower at the end of exercise for Gelda (1.38 ± 0.89 mg/min/cm2), L‐NAME (1.16 ± 0.69 mg/min/cm2) and L+G (1.37 ± 0.79 mg/min/cm2) sites, relative to Control (1.51 ± 0.93 mg/min/cm2) (all P<0.05). Furthermore, sweating was reduced at the L‐NAME site relative to both Gelda and L+G sites (both P<0.05). In summary, these results demonstrate that in healthy habitually active older adults exercising in the heat, HSP90 inhibition does not influence cutaneous vasodilation, despite a clear role for NO in this response. Conversely, HSP90 does attenuate the sweating response in this group. The underlying reasons for the differing effects of HSP90 inhibition on cutaneous vasodilation and sweating between younger and older adults require further investigation.Support or Funding InformationFunding support: Canadian Institutes of Health Research (held by Dr. Kenny).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.