Reflex cutaneous vasodilation: Influences of primary human aging and hypertensive vascular pathology.

摘要

Reflex cutaneous vasodilation is attenuated with primary human aging and hypertensive vascular pathology, rendering these populations more vulnerable to complications from heat-related illness. Full expression of reflex cutaneous vasodilation is dependent on functional nitric oxide (NO), which is reduced with primary human aging and hypertensive vascular pathology. NO bioavailability may be decreased by (1) upregulated arginase (Arg) activity, which reciprocally regulates the NO-synthase (NOS) substrate L-arginine (L-arg) and/or (2) increased oxidant stress. Furthermore, there may be a mechanistic link between upregulated Arg activity and increased oxidant stress through NOS uncoupling. Therefore, the purpose of this series of experiments was to investigate the underlying mechanisms mediating impaired reflex cutaneous vasodilation in aged and hypertensive cutaneous vasculature.; In the first study we investigated age-related alterations in exogenous acetylcholine-induced vasodilation. While acetylcholine is capable of modulating reflexmediated vasodilation, the precise mechanisms through which acetylcholine induces vasodilation and whether those downstream mechanisms change with aging are unclear. We tested the hypotheses that both NO- and prostanoid-mediated pathways contribute to exogenous acetylcholine-induced vasodilation and that both are attenuated with advanced age. We concluded that acetylcholine directly induces cutaneous vasodilation through prostanoid and non-NO-, non-prostanoid-dependent pathways. Further, older subjects have a diminished prostanoid contribution to acetylcholineinduced vasodilation.; In the second study we hypothesized that increased Arg activity contributes to attenuated vasodilation in aged skin by limiting L-arg for NOS-mediated NO synthesis. For all whole body heating studies reflex vasodilation was induced by using a water-perfused suit to increase oral temperature (Tor) 0.8-1.0°C. Increasing L-arg for NO synthesis by either Arg inhibition or direct Larg supplementation abolishes the age-related deficit in reflex cutaneous vasodilation.; The third study tested the hypothesis that age-related increases in oxidant stress attenuates reflex cutaneous vasodilation, therefore acute antioxidant administration alone and combined with Arg inhibition to increase L-arginine availability would increase reflex cutaneous vasodilation in aged skin. Acute Asc supplementation increased reflex cutaneous vasodilation in aged skin. When combined with Arg inhibition to increase L-arg availability Asc supplementation resulted in a further increase in vasodilation above Asc alone, effectively restoring cutaneous vascular conductance to the level of young subjects.; In the fourth study we tested the hypothesized that NO-dependent vasodilation would be attenuated in essential hypertensive human skin due to upregulated Arg activity and acute Arg inhibition or L-arg supplementation would augment reflex cutaneous vasodilation. Vasodilation is attenuated with HTN due to decreased NO-dependent vasodilation and can be augmented with Arg inhibition but not L-arg supplementation, suggesting that Arg is upregulated with HTN.; In the fifth study we tested the hypothesis that increased oxidant stress contributed to attenuated NO-dependent reflex cutaneous vasodilation in hypertensive human subjects, further antioxidant supplementation, alone and combined with Arg inhibition would augment NO-dependent cutaneous vasodilation. Antioxidant supplementation alone or combined with Arg inhibition augments attenuated reflex cutaneous vasodilation in HTN skin through NO- and non-NO-dependent mechanisms. (Abstract shortened by UMI.)