Statin Therapy Enhances Reflex Cutaneous Vasodilation in Formerly Hypercholesterolemic Older Adults by Improving Neurovascular Coupling

Reflex cutaneous vasodilation in response to passive heating is attenuated in human aging. This diminished response is mediated, in part, by age-associated reductions in endothelial function; however, the contribution of altered skin sympathetic nervous system activity (SSNA) is unknown. We hypothesized that 1) healthy older adults would demonstrate blunted SSNA responses to increased core temperature compared with young adults and 2) the decreased SSNA response would be associated with attenuated cutaneous vasodilation. Reflex vasodilation was elicited in 13 young [23 ± 1 (SE) yr] and 13 older (67 ± 2 yr) adults using a water-perfused suit to elevate esophageal temperature by 1.0°C. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry) in the innervated dermatome (the dorsum of foot) were continuously measured. SSNA was normalized to, and expressed as, a percentage of baseline. Cutaneous vascular conductance (CVC) was calculated as flux/mean arterial pressure and expressed as a percentage of maximal CVC (local heating, 43°C). Reflex vasodilation was attenuated in older adults ( P < 0.001). During heating, SSNA increased in both groups ( P < 0.05); however, the response was significantly blunted in older adults ( P = 0.01). The increase in SSNA during heating was linearly related to cutaneous vasodilation in both young ( R2 = 0.87 ± 0.02, P < 0.01) and older ( R2 = 0.76 ± 0.05, P < 0.01) adults; however, slope of the linear regression between ΔSSNA and ΔCVC was reduced in older compared with young (older: 0.05 ± 0.01 vs. young: 0.08 ± 0.01; P < 0.05). These data demonstrate that age-related impairments in reflex cutaneous vasodilation are mediated, in part, by blunted efferent SSNA during hyperthermia.

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iNOS-dependent sweating and eNOS-dependent cutaneous vasodilation are evident in younger adults, but are diminished in older adults exercising in the heat

Journal of Applied Physiology ◽

10.1152/japplphysiol.00714.2015 ◽

2016 ◽

Vol 120 (3) ◽

pp. 318-327 ◽

Cited By ~ 34

Author(s):

Naoto Fujii ◽

Robert D. Meade ◽

Lacy M. Alexander ◽

Pegah Akbari ◽

Imane Foudil-bey ◽

...

Keyword(s):

Older Adults ◽

Intermittent Exercise ◽

Sweat Rate ◽

Fixed Rate ◽

Younger Adults ◽

Physically Active ◽

Cutaneous Vasodilation ◽

Inos Inhibitor ◽

Oxide Synthase ◽

Inos Inhibition

Nitric oxide synthase (NOS) contributes to sweating and cutaneous vasodilation during exercise in younger adults. We hypothesized that endothelial NOS (eNOS) and neuronal NOS (nNOS) mediate NOS-dependent sweating, whereas eNOS induces NOS-dependent cutaneous vasodilation in younger adults exercising in the heat. Further, aging may upregulate inducible NOS (iNOS), which may attenuate sweating and cutaneous vasodilator responses. We hypothesized that iNOS inhibition would augment sweating and cutaneous vasodilation in exercising older adults. Physically active younger ( n = 12, 23 ± 4 yr) and older ( n = 12, 60 ± 6 yr) adults performed two 30-min bouts of cycling at a fixed rate of metabolic heat production (400 W) in the heat (35°C). Sweat rate and cutaneous vascular conductance (CVC) were evaluated at four intradermal microdialysis sites with: 1) lactated Ringer (control), 2) nNOS inhibitor (nNOS-I, NPLA), 3) iNOS inhibitor (iNOS-I, 1400W), or 4) eNOS inhibitor (eNOS-I, LNAA). In younger adults during both exercise bouts, all inhibitors decreased sweating relative to control, albeit a lower sweat rate was observed at iNOS-I compared with eNOS-I and nNOS-I sites (all P < 0.05). CVC at the eNOS-I site was lower than control in younger adults throughout the intermittent exercise protocol (all P < 0.05). In older adults, there were no differences between control and iNOS-I sites for sweating and CVC during both exercise bouts (all P > 0.05). We show that iNOS and eNOS are the main contributors to NOS-dependent sweating and cutaneous vasodilation, respectively, in physically active younger adults exercising in the heat, and that iNOS inhibition does not alter sweating or cutaneous vasodilation in exercising physically active older adults.

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.91215.2008 ◽

2009 ◽

Vol 106 (2) ◽

pp. 500-505 ◽

Cited By ~ 20

Author(s):

Lacy A. Holowatz ◽

W. Larry Kenney

Keyword(s):

Low Dose ◽

Aspirin Therapy ◽

Oral Temperature ◽

Middle Aged ◽

Doppler Flowmetry ◽

Healthy Humans ◽

Cutaneous Vasodilation ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Reflex Cutaneous Vasodilation

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 ± 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 ± 3 yr) subjects, with one site serving as a control (Ringer) and the other NOS inhibited (NOS inhibited: 10 mM NG-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 = flux/mean arterial pressure) and normalized to maximal CVC (CVCmax; 28 mM sodium nitroprusside). CVCmax was not affected by either aspirin or NOS inhibition. The plateau in cutaneous vasodilation during heating (change in oral temperature = 1.0°C) was significantly attenuated in the aspirin group (aspirin: 25 ± 3% CVCmax vs. no aspirin: 50 ± 7% CVCmax, P < 0.001 between groups). NOS inhibition significantly attenuated %CVCmax in both groups (aspirin: 17 ± 2% CVCmax, no aspirin: 23 ± 3% CVCmax; P < 0.001 vs. control), but this attenuation was less in the no-aspirin treatment group ( P < 0.001). This is the first observation that chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation through both COX- and NOS-dependent mechanisms.

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Nitric oxide and attenuated reflex cutaneous vasodilation in aged skin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00871.2002 ◽

2003 ◽

Vol 284 (5) ◽

pp. H1662-H1667 ◽

Cited By ~ 98

Author(s):

Lacy A. Holowatz ◽

Belinda L. Houghton ◽

Brett J. Wong ◽

Brad W. Wilkins ◽

Aaron W. Harding ◽

...

Keyword(s):

Nitric Oxide ◽

Core Temperature ◽

The Elderly ◽

Doppler Flowmetry ◽

Cutaneous Vasodilation ◽

Forearm Skin ◽

Vascular Responsiveness ◽

Older Subjects ◽

Young Subjects ◽

Reflex Cutaneous Vasodilation

Thermoregulatory cutaneous vasodilation is diminished in the elderly. The goal of this study was to test the hypothesis that a reduction in nitric oxide (NO)-dependent mechanisms contributes to the attenuated reflex cutaneous vasodilation in older subjects. Seven young (23 ± 2 yr) and seven older (71 ± 6 yr) men were instrumented with two microdialysis fibers in the forearm skin. One site served as control (Ringer infusion), and the second site was perfused with 10 mM N G-nitro-l-arginine methyl ester to inhibit NO synthase (NOS) throughout the protocol. Water-perfused suits were used to raise core temperature 1.0°C. Red blood cell (RBC) flux was measured with laser-Doppler flowmetry over each microdialysis fiber. Cutaneous vascular conductance (CVC) was calculated as RBC flux per mean arterial pressure, with values expressed as a percentage of maximal vasodilation (infusion of 28 mM sodium nitroprusside). NOS inhibition reduced CVC from 75 ± 6% maximal CVC (CVCmax) to 53 ± 3% CVCmax in the young subjects and from 64 ± 5% CVCmax to 29 ± 2% CVCmax in the older subjects with a 1.0°C rise in core temperature. Thus the relative NO-dependent portion of cutaneous active vasodilation (AVD) accounted for ∼23% of vasodilation in the young subjects and 60% of the vasodilation in the older subjects at this level of hyperthermia ( P < 0.001). In summary, NO-mediated pathways contributed more to the total vasodilatory response of the older subjects at high core temperatures. This suggests that attenuated cutaneous vasodilation with age may be due to a reduction in, or decreased vascular responsiveness to, the unknown neurotransmitter(s) mediating AVD.

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TRPV‐1 channels contribute to local and reflex cutaneous vasodilation in humans

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.991.21 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Brett J. Wong ◽

Sarah M. Fieger ◽

Carl J. Ade

Keyword(s):

Cutaneous Vasodilation ◽

Reflex Cutaneous Vasodilation

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Systemic low-dose aspirin and clopidogrel independently attenuate reflex cutaneous vasodilation in middle-aged humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.01362.2009 ◽

2010 ◽

Vol 108 (6) ◽

pp. 1575-1581 ◽

Cited By ~ 14

Author(s):

Lacy A. Holowatz ◽

John D. Jennings ◽

James A. Lang ◽

W. Larry Kenney

Keyword(s):

Blood Flow ◽

Skin Blood Flow ◽

Low Dose ◽

Middle Aged ◽

Cutaneous Vasodilation ◽

Dose Aspirin ◽

Receptor Inhibition ◽

Low Dose Aspirin ◽

Adp Receptor ◽

Reflex Cutaneous Vasodilation

Chronic systemic platelet cyclooxygenase (COX) inhibition with low-dose aspirin [acetylsalicylic acid (ASA)] significantly attenuates reflex cutaneous vasodilation in middle-aged humans, whereas acute, localized, nonisoform-specific inhibition of vascular COX with intradermal administration of ketorolac does not alter skin blood flow during hyperthermia. Taken together, these data suggest that platelets may be involved in reflex cutaneous vasodilation, and this response is inhibited with systemic pharmacological platelet inhibition. We hypothesized that, similar to ASA, specific platelet ADP receptor inhibition with clopidogrel would attenuate reflex vasodilation in middle-aged skin. In a double-blind crossover design, 10 subjects (53 ± 2 yr) were instrumented with four microdialysis fibers for localized drug administration and heated to increase body core temperature [oral temperature (Tor)] 1°C during no systemic drug (ND), and after 7 days of systemic ASA (81 mg) and clopidogrel (75 mg) treatment. Skin blood flow (SkBF) was measured using laser-Doppler flowmetry over each site assigned as 1) control, 2) nitric oxide synthase inhibited (NOS-I; 10 mM NG-nitro-l-arginine methyl ester), 3) COX inhibited (COX-I; 10 mM ketorolac), and 4) NOS-I + COX-I. Data were normalized and presented as a percentage of maximal cutaneous vascular conductance (%CVCmax; 28 mM sodium nitroprusside + local heating to 43°C). During ND conditions, SkBF with change (Δ) in Tor = 1.0°C was 56 ± 3% CVCmax. Systemic low-dose ASA and clopidogrel both attenuated reflex vasodilation (ASA: 43 ± 3; clopidogrel: 32 ± 3% CVCmax; both P < 0.001). In all trials, localized COX-I did not alter SkBF during significant hyperthermia (ND: 56 ± 7; ASA: 43 ± 5; clopidogrel: 35 ± 5% CVCmax; all P > 0.05). NOS-I attenuated vasodilation in ND and ASA (ND: 28 ± 6; ASA: 25 ± 4% CVCmax; both P < 0.001), but not with clopidogrel (27 ± 4% CVCmax; P > 0.05). NOS-I + COX-I was not different compared with NOS-I alone in either systemic treatment condition. Both systemic ASA and clopidogrel reduced the time required to increase Tor 1°C (ND: 58 ± 3 vs. ASA: 45 ± 2; clopidogrel: 39 ± 2 min; both P < 0.001). ASA-induced COX and specific platelet ADP receptor inhibition attenuate reflex vasodilation, suggesting platelet involvement in reflex vasodilation through the release of vasodilating factors.

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Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide-dependent mechanisms in aged human skin

Journal of Applied Physiology ◽

10.1152/japplphysiol.01257.2011 ◽

2012 ◽

Vol 112 (5) ◽

pp. 791-797 ◽

Cited By ~ 55

Author(s):

Anna E. Stanhewicz ◽

Rebecca S. Bruning ◽

Caroline J. Smith ◽

W. Larry Kenney ◽

Lacy A. Holowatz

Keyword(s):

Nitric Oxide ◽

Human Skin ◽

Oxidant Stress ◽

Local Heat ◽

Whole Body ◽

Mean Body Temperature ◽

Doppler Flowmetry ◽

Cutaneous Vasodilation ◽

Aged Skin ◽

Reflex Cutaneous Vasodilation

Functional constitutive nitric oxide synthase (NOS) is required for full expression of reflex cutaneous vasodilation that is attenuated in aged skin. Both the essential cofactor tetrahydrobiopterin (BH4) and adequate substrate concentrations are necessary for the functional synthesis of nitric oxide (NO) through NOS, both of which are reduced in aged vasculature through increased oxidant stress and upregulated arginase, respectively. We hypothesized that acute local BH4 administration or arginase inhibition would similarly augment reflex vasodilation in aged skin during passive whole body heat stress. Four intradermal microdialysis fibers were placed in the forearm skin of 11 young (22 ± 1 yr) and 11 older (73 ± 2 yr) men and women for local infusion of 1) lactated Ringer, 2) 10 mM BH4, 3) 5 mM ( S)-(2-boronoethyl)-l-cysteine + 5 mM Nω-hydroxy-nor-l-arginine to inhibit arginase, and 4) 20 mM NG-nitro-l-arginine methyl ester (l-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced. After a 1.0°C rise in oral temperature (Tor), mean body temperature was clamped and 20 mM l-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/mean arterial pressure) and expressed as a percentage of maximum (%CVCmax; 28 mM sodium nitroprusside and local heat, 43°C). Vasodilation was attenuated at the control site of the older subjects compared with young beginning at a 0.3°C rise in Tor. BH4 and arginase inhibition both increased vasodilation in older (BH4: 55 ± 5%; arginase-inhibited: 47 ± 5% vs. control: 37 ± 3%, both P < 0.01) but not young subjects compared with control (BH4: 51 ± 4%CVCmax; arginase-inhibited: 55 ± 4%CVCmax vs. control: 56 ± 6%CVCmax, both P > 0.05) at a 1°C rise in Tor. With a 1°C rise in Tor, local BH4 increased NO-dependent vasodilation in the older (BH4: 31.8 ± 2.4%CVCmax vs. control: 11.7 ± 2.0%CVCmax, P < 0.001) but not the young (BH4: 23 ± 4%CVCmax vs. control: 21 ± 4%CVCmax, P = 0.718) subject group. Together these data suggest that reduced BH4 contributes to attenuated vasodilation in aged human skin and that BH4 NOS coupling mechanisms may be a potential therapeutic target for increasing skin blood flow during hyperthermia in older humans.

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Local ascorbate administration augments NO- and non-NO-dependent reflex cutaneous vasodilation in hypertensive humans

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00295.2007 ◽

2007 ◽

Vol 293 (2) ◽

pp. H1090-H1096 ◽

Cited By ~ 70

Author(s):

Lacy A. Holowatz ◽

W. Larry Kenney

Keyword(s):

Local Heating ◽

Oxidant Stress ◽

Control Site ◽

No Synthase ◽

Oral Temperature ◽

Antioxidant Supplementation ◽

Doppler Flowmetry ◽

Cutaneous Vasodilation ◽

Reflex Cutaneous Vasodilation ◽

Cutaneous Vascular Conductance

Full expression of reflex cutaneous vasodilation (VD) is dependent on nitric oxide (NO) and is attenuated with essential hypertension. Decreased NO-dependent VD may be due to 1) increased oxidant stress and/or 2) decreased l-arginine availability through upregulated arginase activity, potentially leading to increased superoxide production through uncoupled NO synthase (NOS). The purpose of this study was to determine the effect of antioxidant supplementation (alone and combined with arginase inhibition) on attenuated NO-dependent reflex cutaneous VD in hypertensive subjects. Nine unmedicated hypertensive [HT; mean arterial pressure (MAP) = 112 ± 1 mmHg] and nine age-matched normotensive (NT; MAP = 81 ± 10 mmHg) men and women were instrumented with four intradermal microdialysis (MD) fibers: control (Ringer), NOS inhibited (NOS-I; 10 mM NG-nitro-l-arginine), l-ascorbate supplemented (Asc; 10 mM l-ascorbate), and Asc + arginase inhibited [Asc+A-I; 10 mM l-ascorbate + 5 mM ( S)-(2-boronoethyl)-l-cysteine-HCl + 5 mM Nω-hydroxy- nor-l-arginine]. Oral temperature was increased by 0.8°C via a water-perfused suit. NG-nitro-l-arginine was then ultimately perfused through all MD sites to quantify the change in VD due to NO. Red blood cell flux was measured by laser-Doppler flowmetry over each skin MD site, and cutaneous vascular conductance (CVC) was calculated (CVC = flux/MAP) and normalized to maximal CVC (%CVCmax; 28 mM sodium nitroprusside + local heating to 43°C). During the plateau in skin blood flow (ΔTor = 0.8°C), cutaneous VD was attenuated in HT skin (NT: 42 ± 4, HT: 35 ± 3 %CVCmax; P < 0.05). Asc and Asc+A-I augmented cutaneous VD in HT (Asc: 57 ± 5, Asc+A-I: 53 ± 6 %CVCmax; P < 0.05 vs. control) but not in NT. %CVCmax after NOS-I in the Asc- and Asc+A-I-treated sites was increased in HT (Asc: 41 ± 4, Asc+A-I: 40 ± 4, control: 29 ± 4; P < 0.05). Compared with the control site, the change in %CVCmax within each site after NOS-I was greater in HT (Asc: −19 ± 4, Asc+A-I: −17 ± 4, control: −9 ± 2; P < 0.05) than in NT. Antioxidant supplementation alone or combined with arginase inhibition augments attenuated reflex cutaneous VD in hypertensive skin through NO- and non-NO-dependent mechanisms.

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Transient receptor potential vanilloid type 1 channels contribute to reflex cutaneous vasodilation in humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.00209.2012 ◽

2012 ◽

Vol 112 (12) ◽

pp. 2037-2042 ◽

Cited By ~ 26

Author(s):

Brett J. Wong ◽

Sarah M. Fieger

Keyword(s):

Blood Flow ◽

Skin Blood Flow ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Whole Body ◽

Transient Receptor Potential Vanilloid ◽

Cutaneous Vasodilation ◽

Transient Receptor ◽

Reflex Cutaneous Vasodilation

Mechanisms underlying the cutaneous vasodilation in response to an increase in core temperature remain unresolved. The purpose of this study was to determine a potential contribution of transient receptor potential vanilloid type 1 (TRPV-1) channels to reflex cutaneous vasodilation. Twelve subjects were equipped with four microdialysis fibers on the ventral forearm, and each site randomly received 1) 90% propylene glycol + 10% lactated Ringer (vehicle control); 2) 10 mM l-NAME; 3) 20 mM capsazepine to inhibit TRPV-1 channels; 4) combined 10 mM l-NAME + 20 mM capsazepine. Whole body heating was achieved via water-perfused suits sufficient to raise oral temperature at least 0.8°C above baseline. Maximal skin blood flow was achieved by local heating to 43°C and infusion of 28 mM nitroprusside. Systemic arterial pressure (SAP) was measured, and skin blood flow was monitored via laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF/SAP and normalized to maximal vasodilation (%CVCmax). Capsazepine sites were significantly reduced compared with control (50 ± 4%CVCmax vs. 67 ± 5%CVCmax, respectively; P < 0.05). l-NAME (33 ± 3%CVCmax) and l-NAME + capsazepine (30 ± 4%CVCmax) sites were attenuated compared with control ( P < 0.01) and capsazepine ( P < 0.05); however, there was no difference between l-NAME and combined l-NAME + capsazepine. These data suggest TRPV-1 channels participate in reflex cutaneous vasodilation and TRPV-1 channels may account for a portion of the NO component. TRPV-1 channels may have a direct neural contribution or have an indirect effect via increased arterial blood temperature. Whether the TRPV-1 channels directly or indirectly contribute to reflex cutaneous vasodilation remains uncertain.

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Sensory nerves and nitric oxide contribute to reflex cutaneous vasodilation in humans

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00464.2012 ◽

2013 ◽

Vol 304 (8) ◽

pp. R651-R656 ◽

Cited By ~ 25

Author(s):

Brett J. Wong

Keyword(s):

Nitric Oxide ◽

Heat Stress ◽

Core Temperature ◽

Sensory Nerve ◽

Sensory Nerves ◽

Whole Body ◽

Oral Temperature ◽

Doppler Flowmetry ◽

Cutaneous Vasodilation ◽

Reflex Cutaneous Vasodilation

We tested the hypothesis that inhibition of cutaneous sensory nerves would attenuate reflex cutaneous vasodilation in response to an increase in core temperature. Nine subjects were equipped with four microdialysis fibers on the forearm. Two sites were treated with topical anesthetic EMLA cream for 120 min. Sensory nerve inhibition was verified by lack of sensation to a pinprick. Microdialysis fibers were randomly assigned as 1) lactated Ringer (control); 2) 10 mM nitro-l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase; 3) EMLA + lactated Ringer; and 4) EMLA + l-NAME. Laser-Doppler flowmetry was used as an index of skin blood flow, and blood pressure was measured via brachial auscultation. Subjects wore a water-perfused suit, and oral temperature was monitored as an index of core temperature. The suit was perfused with 50°C water to initiate whole body heat stress to raise oral temperature 0.8°C above baseline. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVCmax). There was no difference in CVC between control and EMLA sites (67 ± 5 vs. 69 ± 6% CVCmax), but the onset of vasodilation was delayed at EMLA compared with control sites. The l-NAME site was significantly attenuated compared with control and EMLA sites (45 ± 5% CVCmax; P < 0.01). Combined EMLA + l-NAME site (25 ± 6% CVCmax) was attenuated compared with control and EMLA ( P < 0.001) and l-NAME only ( P < 0.01). These data suggest cutaneous sensory nerves contribute to reflex cutaneous vasodilation during the early, but not latter, stages of heat stress, and full expression of reflex cutaneous vasodilation requires functional sensory nerves and NOS.

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