Age-related Impairments in Nitric Oxide-dependent Cutaneous Vasodilation and Sweating During Exercise: Roles for Oxidative Stress and Arginase?

Abstract

This thesis sought to evaluate whether the impairments in nitric oxide (NO)-dependent cutaneous vasodilation and sweating observed in older adults during exercise in the heat stem from age-related increases in oxidative stress and/or arginase activity. Furthermore, we assessed whether changes in the sensitivity to NO at the level of the end-organ (i.e., cutaneous vasculature and sweat gland) also contribute. A total of 20 young (age, 23 ± 3 yrs) and 28 older (age, 63 ± 7 yrs) males completed one of two intermittent exercise protocols that consisted of two 30-min bouts of semi-recumbent cycling in the heat (35˚C) at a rate of metabolic heat production of 500 (protocol I; 11 young, 19 older) or 400 (protocol II; 9 young, 9 older) W. Each exercise bout was followed by a 20-min recovery period. During each protocol, local cutaneous vascular conductance (CVC; laser-Doppler flowmetry/mean arterial pressure) and sweat rate (SR, ventilated capsule) were continuously measured at four forearm skin sites. In protocol I, each forearm skin site was continuously perfused via intradermal microdialysis with either: 1) lactated Ringer’s serving as a control (Control); 2) 10 mM NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor; 3) 10 mM ascorbate (Ascorbate), a non-selective antioxidant or 4) a combination of 10 mM ascorbate and 10 mM L-NAME (L-NAME + Ascorbate). In protocol II, the Ascorbate and L-NAME + Ascorbate skin sites were replaced with 5 mM Nω-hydroxy-nor-Arginine + 5 mM S-(2-boronoethyl)-L-cysteine to inhibit arginase activity (Nor-NOHA+BEC) and 1 µM sodium nitroprusside, a nitric oxide donor (SNP). In the young adults during protocol I, CVC was reduced relative to Control at L-NAME (both P<0.01) and L-NAME + Ascorbate (both P≤0.03) but similar to Control at Ascorbate (both P≥0.26). In the older adults, CVC was reduced from Control during both exercise bouts at L-NAME (both P≤0.02) but not Ascorbate (both P≥0.09) or L-NAME + Ascorbate (both P≥0.15). While L-NAME (both P<0.04) and L-NAME + Ascorbate (both P<0.04) attenuated SR in the younger adults during exercise (no effect of Ascorbate; both P≥0.36), no differences between Control and any treatment site were observed in the older adults (P=0.42). However, correlational analysis revealed a moderate negative correlation between between VO2peak and the change in SR from control at the Ascorbate site during both exercise bouts (-0.55≤r≤-0.54; both P=0.02) exercise. Furthermore, the change in SR from Control at L-NAME + Ascorbate was also found to be negatively correlated with VO2peak in the second (r=-0.54; P=0.02) but not first (r=-0.42; P=0.08) exercise bout. In protocol II, CVC was reduced from Control at L-NAME in the young and older adults during both (both P<0.01) and the first (P=0.05) exercise bout, respectively. Furthermore, SR was reduced from Control in the young (both P≤0.03) but not older (P=0.28) adults at the L-NAME skin site. However, no influence of Nor-NOHA+BEC or SNP was observed in either age group for both CVC (all P≥0.38) and SR (P=0.28). This thesis demonstrates that age-related increases in oxidative stress influence cutaneous vasodilation during exercise via mechanisms independent of NO. Furthermore, the current findings suggest an effect of oxidative stress on NO-independent SR in older adults but that secondary factors (i.e., aerobic fitness and/or physical activity level) may play a modulatory role. Finally, the results of this thesis demonstrate that, during exercise in the heat, neither elevated arginase activity nor changes in the sensitivity of the thermoregulatory end-organs to NO effect the CVC and SR responses in older adults.