Acute ascorbate supplementation alone or combined with arginase inhibition augments reflex cutaneous vasodilation in aged human skin

Holowatz, Lacy A.; Thompson, Caitlin S.; Kenney, W. Larry

doi:10.1152/ajpheart.00648.2006

Cited by 82 publications

(96 citation statements)

References 38 publications

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“…With ageing, there is a significant attenuation in the initial sensory axon reflex, as well as a reduction in the eNOS-dependent plateau. Although the underlying mechanisms mediating this decline are not fully defined in the ageing microvasculature, age-related changes in oxidant stress as well as substrate and co-factor availability contribute to endothelial dysfunction with ageing and are probably contributing factors [4,5,7]. As the skin blood flow response to local heating is predominantly eNOS dependent, local heating is a valuable method to non-invasively assess endothelium-dependent vasodilatation in vivo in the human vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…The decreased NO bioavailability in aged skin results from a decrease in NO production by up-regulated vascular arginase and increased NOS uncoupling, with increased oxidant stress and reduced co-factor bioavailability [6,7,13,37]. Although the contributions and identities of the co-transmitters in human skin are not fully known, many of these co-transmitters converge on the NO pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Age-related impairments in NO-dependent vasodilatation are due, in part, to decreases in tetrahydrobiopterin (BH 4 ) bioavailability [4,5], and increases in arginase activity [6,7] and oxidant stress [7,8]. BH 4 is required to maintain the functional conformation of the nitric oxide synthase (NOS) dimer for NO production and is reduced with ageing as a result of decreased synthesis and increased oxidation by free radicals [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms

2015

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Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22 ± 1 years) and 11 older (O: 71 ± 3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O = 82 ± 3 vs Y = 96 ± 1, P = 0.002) and NO-dependent vasodilatation (%CVCmax: O = 26 ± 6% vs Y = 49 ± 5, P = 0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax = 91 ± 2, P = 0.03) and NO-dependent (%CVCmax = 43 ± 9%, P = 0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O = 31 ± 8 vs Y = 44 ± 5, P = 0.001) and NO-dependent (%CVCmax: O = 9 ± 2 vs Y = 21 ± 2, P = 0.003) vasodilatation. Folic acid increased CVC (%CVCmax = 47 ± 5%, P = 0.001) and NO-dependent vasodilatation (20 ± 3%, P = 0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms

2015

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“…A functional loss of active cholinergic vasodilation cotransmitter function and dysfunction of second-messenger pathways (i.e., nitric oxide bioavailability) (8,11,12,31) contribute to attenuated cutaneous vasodilatory responses to elevations in core temperature (T core ), hindering convective heat loss. An age-related decline in thermoregulatory sweating further compromises heat loss and increases thermal strain in warm ambient conditions and during exercise.…”

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confidence: 99%

Nonuniform, age-related decrements in regional sweating and skin blood flow

Smith

Alexander

Kenney

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Smith CJ, Alexander LM, Kenney WL. Nonuniform, age-related decrements in regional sweating and skin blood flow. Am J Physiol Regul Integr Comp Physiol 305: R877-R885, 2013. First published August 7, 2013 doi:10.1152/ajpregu.00290.2013.-Aging is associated with attenuated thermoregulatory function that varies regionally over the body. Decrements in vasodilation and sweating are well documented with age, yet limited data are available concerning the regional relation between these responses. We aimed to examine age-related alterations in the relation between regional sweating (RSR) and skin blood flow (SkBF) to thermal and pharmacological stimuli. Four microdialysis fibers were inserted in the ventral forearm, abdomen, thigh, and lower back of eight healthy aged subjects (64 Ϯ 7 yr) and nine young (23 Ϯ 3 yr) during 1) ACh dose response (1 ϫ 10 Ϫ7 to 0.1 M, mean skin temperature 34°C) and 2) passive whole body heating to ⌬1°C rise in oral temperature (Tor). RSR and SkBF were measured over each microdialysis membrane using ventilated capsules and laser-Doppler flowmetry. Maximal SkBF was measured at the end of both protocols (50 mM SNP). Regional sweating thresholds and RSR were attenuated in aged vs. young at all sites (P Ͻ 0.0001) during whole body heating. Vasodilation thresholds were similar between groups (P Ͼ 0.05). Attenuated SkBF were observed at the arm and back in the aged, representing 56 and 82% of those in the young at these sites, respectively (0.5 ⌬Tor). During ACh perfusion, SkBF (P ϭ 0.137) and RSR were similar between groups (P ϭ 0.326). Together these findings suggest regional age-related decrements in heat-activated sweat gland function but not cholinergic sensitivity. Functional consequences of such thermoregulatory impairment include the compromised ability of older individuals to defend core temperature during heat exposure and a subsequently greater susceptibility to heat-related illness and injury.sweating; aging; laser-Doppler flowmetry; skin blood flow; sweating HUMAN AGING IS ASSOCIATED with altered thermoregulatory function during both passive and exercise-induced hyperthermia, including attenuated reflex cutaneous vasodilation (26) and eccrine sweating responses (3,18,24). A functional loss of active cholinergic vasodilation cotransmitter function and dysfunction of second-messenger pathways (i.e., nitric oxide bioavailability) (8,11,12,31) contribute to attenuated cutaneous vasodilatory responses to elevations in core temperature (T core ), hindering convective heat loss. An age-related decline in thermoregulatory sweating further compromises heat loss and increases thermal strain in warm ambient conditions and during exercise. Reduced evaporative heat loss from the skin surface results from a decline in thermoregulatory sweating, due to a decreased thermal sensitivity (32) and atrophy of the sweat glands (17, 19), producing a lower sweat output per gland (23,24,39).Regional variation in sweating and skin blood flow (SkBF) responses to passive heating are well documented (29); howev...

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“…Human aging in the absence of overt pathology is associated with an attenuated rise in skin blood flow during hyperthermia (10,(13)(14)(15) due to a reduction in NO-and non-NO-dependent vasodilation. Low-dose aspirin therapy is increasingly recommended in middle-aged and elderly populations for atherothrombotic disease prevention (29); however, the combined effects of primary human aging and inhibition of COX-dependent cutaneous vasodilatory pathways with low-dose aspirin may significantly impact reflex-mediated thermoregulatory mechanisms, including the potential to functionally lower the critical psychrometric limits for heat gain in individuals taking chronic aspirin therapy.…”

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Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation in middle-aged humans

Holowatz

Kenney

2009

Journal of Applied Physiology

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Holowatz LA, Kenney WL. Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation in middle-aged humans. J Appl Physiol 106: 500 -505, 2009. First published November 26, 2008 doi:10.1152/japplphysiol.91215.2008.-Full expression of reflex cutaneous vasodilation is dependent on cyclooxygenase-(COX) and nitric oxide synthase-(NOS) dependent mechanisms. Low-dose aspirin therapy is widely prescribed to inhibit COX-1 in platelets for atherothrombotic prevention. We hypothesized that chronic COX inhibition with daily low-dose aspirin therapy (81 mg) would attenuate reflex vasodilation in healthy human skin. Two microdialysis fibers were placed in forearm skin of seven middle-aged (57 Ϯ 3 yr), normotensive, healthy humans with no preexisting cardiovascular disease, taking daily low-dose aspirin therapy (aspirin: 81 mg), and seven unmedicated, healthy, age-matched control (no aspirin, 55 Ϯ 3 yr) subjects, with one site serving as a control (Ringer) and the other NOS inhibited (NOS inhibited: 10 mM N G -nitro-L-arginine methyl ester). Red cell flux was measured over each site by laser-Doppler flowmetry, as reflex vasodilation was induced by increasing core temperature (oral temperature) 1.0°C using a water-perfused suit. Cutaneous vascular conductance (CVC) was calculated (CVC ϭ flux/mean arterial pressure) and normalized to maximal CVC (CVC max ; 28 mM sodium nitroprusside). CVC max was not affected by either aspirin or NOS inhibition. The plateau in cutaneous vasodilation during heating (change in oral temperature ϭ 1.0°C) was significantly attenuated in the aspirin group (aspirin: 25 Ϯ 3% CVC max vs. no aspirin: 50 Ϯ 7% CVC max, P Ͻ 0.001 between groups). NOS inhibition significantly attenuated %CVC max in both groups (aspirin: 17 Ϯ 2% CVCmax, no aspirin: 23 Ϯ 3% CVC max; P Ͻ 0.001 vs. control), but this attenuation was less in the no-aspirin treatment group (P Ͻ 0.001). This is the first observation that chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation through both COX-and NOS-dependent mechanisms.thermoregulation; prostaglandins; cyclooxygenase; nitric oxide AS CORE TEMPERATURE RISES, skin blood flow is first increased by withdrawal of adrenergic vasoconstrictor tone, and then, upon reaching a specific core temperature threshold, both sweating and active reflex cutaneous vasodilation occur (31). Reflex vasodilation is activated by cholinergic cotransmission (19) and is mediated by several putative vasodilator mechanisms, including the neurotransmitter vasoactive intestinal peptide (1), histamine receptor activation (38), and neurokinin-1 receptor activation (36). Furthermore, full expression of reflex cutaneous vasodilation is dependent on nitric oxide (NO) synthase-(NOS) (17, 33) and cyclooxygenase-(COX) mediated secondmessenger mechanisms, which purportedly contribute independently to the rise in skin blood flow during hyperthermia (22).Daily low-dose aspirin is the gold standard antiplatelet aggregation therapy for primary and secondary prevention of atherothrombotic disea...

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Acute ascorbate supplementation alone or combined with arginase inhibition augments reflex cutaneous vasodilation in aged human skin

Cited by 82 publications

References 38 publications

Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms

Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms

Nonuniform, age-related decrements in regional sweating and skin blood flow

Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation in middle-aged humans

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