W Larry Kenney

Pennsylvania State University, State College, PA, United States

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Publications (146)394.15 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: This brief review is based on a President's Lecture presented at the Annual Meeting of the American College of Sports Medicine in 2013. The purpose of this review is to assess the effects of climate change and consequent increases in environmental heat stress on the aging cardiovascular system. The earth's average global temperature is slowly but consistently increasing, and along with mean temperature changes come increases in heat wave frequency and severity. Extreme passive thermal stress resulting from prolonged elevations in ambient temperature, as well as prolonged physical activity in hot environments, creates a high demand on the left ventricle to pump blood to the skin to dissipate heat. Even healthy aging is accompanied by altered cardiovascular function, which limits the extent to which older individuals can maintain stroke volume, increase cardiac output, and increase skin blood flow when exposed to environmental extremes. In the elderly, the increased cardiovascular demand during heat waves is often fatal due to increased strain on an already compromised left ventricle. Not surprisingly, excess deaths during heat waves 1) occur predominantly in older individuals and 2) are overwhelmingly cardiovascular in origin. Increasing frequency and severity of heat waves coupled with a rapidly growing at-risk population dramatically increases the extent of future untoward health outcomes.
    Medicine and science in sports and exercise 03/2014; · 3.71 Impact Factor
  • R S Bruning, W L Kenney, L M Alexander
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    ABSTRACT: Essential hypertensive humans exhibit attenuated cutaneous nitric oxide (NO)-dependent vasodilation. Using spectral analysis (fast Fourier transformation) we aimed to characterize the skin flowmotion contained in the laser-Doppler flowmetry recordings during local heating-induced vasodilation before and after concurrent pharmacological inhibition of nitric oxide synthase (NOS) in hypertensive and age-matched normotensive men and women. We hypothesized that hypertensive subjects would have lower total power spectral densities (PSD), specifically in the frequency intervals associated with intrinsic endothelial and neurogenic control of the microvasculature. Furthermore, we hypothesized that NOS inhibition would attenuate the endothelial frequency interval. Laser-Doppler flowmetry recordings during local heating experiments from 18 hypertensive (MAP: 108±2mmHg) and 18 normotensive (MAP: 88±2mmHg) men and women were analyzed. Within site NO-dependent vasodilation was assessed by perfusion of a non-specific NOS inhibitor (N(G)-nitro-L-arginine methyl ester; L-NAME) through intradermal microdialysis during the heating-induced plateau in skin blood flow. Local heating-induced vasodilation increased total PSD for all frequency intervals (all p<0.001). Hypertensives had a lower total PSD (p=0.03) and absolute neurogenic frequency intervals (p<0.01) compared to the normotensives. When normalized as a percentage of total PSD, hypertensives had reduced neurogenic (p<0.001) and augmented myogenic contributions (p=0.04) to the total spectrum. NOS inhibition decreased total PSD (p<0.001) for both groups, but hypertensives exhibited lower absolute endothelial (p<0.01), neurogenic (p<0.05), and total PSD (p<0.001) frequency intervals compared to normotensives. These data suggest that essential hypertension results in altered neurogenic and NOS-dependent control of skin flowmotion and support the use of spectral analysis as a non-invasive technique to study vasoreactivity.
    Microvascular Research 01/2014; · 2.93 Impact Factor
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    ABSTRACT: Aging is associated with attenuated thermoregulatory function which 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±7 years) and nine young (23±3 years) during 1) acetylcholine dose response (ACh 1x10(-7) - 0.1 M, mean skin temperature 34°C) and 2) passive whole body heating to Δ1°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 (50mM SNP). Regional sweating thresholds and RSR were attenuated in aged versus young at all sites (p<0.0001) during whole body heating. Vasodilation thresholds were similar between groups (p>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 ΔTor). During ACh perfusion SkBF (p=0.137) and RSR were similar between groups (p= 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.
    AJP Regulatory Integrative and Comparative Physiology 08/2013; · 3.28 Impact Factor
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    ABSTRACT: Reflex vasoconstriction is attenuated in aged skin due to a functional loss of adrenergic vasoconstriction. Bioavailability of tetrahydrobiopterin (BH4), an essential cofactor for catecholamine synthesis, is reduced with aging. Locally-administered BH4 increases vasoconstriction through adrenergic mechanisms in aged human skin. We hypothesized that oral sapropterin (Kuvan®, pharmaceutical BH4) would augment vasoconstriction elicited by whole-body cooling and tyramine perfusion in aged skin. Ten healthy subjects (75±2years) ingested sapropterin (10mg/kg) or placebo in a randomized double-blind crossover design. Venous blood samples were collected prior to, and 3h following, ingestion. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of (1) lactated Ringer's, (2) 5mM BH4, and (3)5mM yohimbine+1mM propranolol (to inhibit adrenergic vasoconstriction). Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasoconstriction was induced by lowering and then clamping whole body skin temperature (Tsk) using a water-perfused suit. Following whole-body cooling, subjects were rewarmed and 1mM tyramine was perfused at each site to elicit endogenous norepinephrine release from the perivascular nerve terminal. Cutaneous vascular conductance was calculated (CVC=LDF/MAP) and expressed as change from baseline (ΔCVC). Plasma BH4 was elevated 3h after ingestion of sapropterin (43.8±3 vs 19.1±2pmol/ml; p<0.001). Sapropterin increased reflex vasoconstriction in the Ringer's site at Tsk≤32.5°C (p<0.05). Local BH4-perfusion augmented reflex vasoconstriction at Tsk≤31.5°C with placebo treatment only(p<0.05). There was no treatment effect on reflex vasoconstriction at the BH4-perfused or Y+P-perfused sites. Sapropterin increased pharmacologically-induced vasoconstriction at the Ringer's site (-0.19±0.03 vs. -0.08±0.02ΔCVC; p=0.01). There was no difference in pharmacologically-induced vasoconstriction between treatments at the BH4-perfused site (-0.16±0.04 vs. -0.14±0.03ΔCVC; p=0.60) or the Y+P-perfused site (-0.05±0.02 vs.-0.06±0.02ΔCVC; p=0.79). Sapropterin increases both reflex (cold-induced) and pharmacologically-induced vasoconstriction through adrenergic mechanisms and may be a viable intervention to improve reflex vasoconstriction in aged humans.
    Journal of Applied Physiology 07/2013; · 3.48 Impact Factor
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    ABSTRACT: Platelet P2Y12-ADP and COX-1 receptor inhibition with oral clopidogrel (CLO) and low dose aspirin (ASA), respectively, attenuates reflex-mediated cutaneous vasodilation, but little is known about how these medications effect local vasodilatory signaling. Reactive hyperemia (RH) results in vasodilation that is mediated by sensory nerves and endothelium-derived hyperpolarization factors (EDHF) through BKCa channels, whereas slow local heating (LH) elicits vasodilation largely through the production of nitric oxide (NO). We hypothesized that CLO and ASA would attenuate locally-mediated cutaneous vasodilation assessed by RH and LH (0.5°C•min(-1)). In a randomized, crossover, double-blind placebo-controlled study, nine healthy men and women (56±1 years) took CLO (75mg), ASA (81mg), and placebo for seven days. Skin blood flow (SkBF) was measured (laser-Doppler flowmetry: LDF) and cutaneous vascular conductance (CVC) was calculated (LDF/MAP) and normalized to maximal CVC (%CVCmax: 43°C and 28mM sodium nitroprusside). RH response parameters including area under the curve (AUC), total hyperemic response (THR), and the decay constant tau (λ) were calculated. NO-dependent vasodilation during LH was assessed by calculating the difference in %CVCmax between a control site and an NO-synthase inhibited site (10mM L-NAME: intradermal microdialysis). CLO augmented the AUC and THR (AUCclo = 3783±342; THRclo = 2306±266%CVCmax•s ) of the RH response compared to ASA (AUCASA=3101±325; THRASA=1695±197%CVCmax•s) and placebo (AUCPlacebo=3000±283; THRPlacebo=1675±170%CVCmax•s; all p<0.0001 vs. CLO). There was no difference in the LH response or calculated NO-dependent vasodilation among treatments (all p>0.05). Oral CLO treatment augments vasodilation during RH but not LH, suggesting that CLO may improve cutaneous microvascular function.
    AJP Regulatory Integrative and Comparative Physiology 06/2013; · 3.28 Impact Factor
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    ABSTRACT: Functional constitutive nitric oxide synthase (NOS) and its cofactor tetrahydrobiopterin(BH4) are required for full reflex cutaneous vasodilation, and are attenuated in primary aging. Acute locally-administered BH4 increases reflex vasodilation through NO-dependent mechanisms in aged skin. We hypothesized that oral sapropterin (Kuvan®, shelf-stable pharmaceutical formulation of BH4) would augment reflex vasodilation in aged human skin during hyperthermia. Nine healthy human subjects (76±1years) ingested sapropterin (10mg/kg) or placebo in a randomized double-blind crossover design. Venous blood samples were collected prior to, and 3h following, ingestion of sapropterin for measurement of plasma BH4. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1)lactated Ringers solution, 2)10mM BH4, and 3)20mM N(G)-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 using a water-perfused suit. At 1°C rise in oral temperature, mean body temperature was clamped and 20mM L-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC=LDF/MAP) and expressed as a percentage of maximum (%CVCmax;28mM sodium nitroprusside and local heat,43°C). Plasma concentrations of BH4 were significantly elevated 3h after ingestion of sapropterin (0h:19.1±2pmol/mlvs.3h:43.8±3pmol/ml;p<0.001). Sapropterin increased NO-dependent vasodilation at control site (placebo:14±1%CVCmaxvs.sapropterin:25±4%CVCmax;p=0.004). Local BH4 administration increased NO-dependent vasodilation compared to control in placebo trials only (control:14±1%CVCmaxvs.BH4-treated:24±3%CVCmax;p=0.02). These data suggest oral sapropterin increases bioavailable BH4 in aged skin microvasculature sufficiently to increase NO synthesis through NOS and that sapropterin may be a viable intervention to increase skin blood flow during hyperthermia in healthy aged humans.
    Journal of Applied Physiology 06/2013; · 3.48 Impact Factor
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    ABSTRACT: When prolonged intense exercise is performed at high ambient temperatures, cardiac output must meet dual demands for increased blood flow to contracting muscle and to the skin. The literature has commonly painted this scenario as a fierce competition, wherein one circulation preserves perfusion at the expense of the other, with the regulated maintenance of blood pressure as the ultimate goal. This review redefines this scenario as commensalism, an integrated balance of regulatory control where one circulation benefits with little functional effect on the other. In young, healthy subjects, arterial pressure rarely falls to any great extent during either extreme passive heating or prolonged dynamic exercise in the heat, nor does body temperature rise disproportionately due to a compromised skin blood flow. Rather, it often takes the superimposition of additional stressors-e.g., dehydration or simulated hemorrhage-upon heat stress to substantially impact blood pressure regulation.
    Arbeitsphysiologie 05/2013; · 2.66 Impact Factor
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    ABSTRACT: Regional variation in sweating over the human body is widely recognized yet variation in vasomotor responses and mechanisms causing this variation remain unclear. This study aimed to explore the relation between regional sweating rates (RSR) and skin blood flow (SkBF) responses to thermal and pharmacological stimuli in young, healthy subjects. In nine subjects (23±3 yrs), intradermal microdialysis (MD) probes were inserted into the ventral forearm, abdomen, thigh, and lower back and perfused with lactated Ringer solution. RSR over each MD membrane were measured using ventilated capsules with a laser-Doppler probe housed in each capsule for measurement of red cell flux (LDF) as an index of SkBF. Subjects completed a whole body heating protocol to 1°C rise in oral temperature, and an acetylcholine dose response (ACh 1x10(-7) - 0.1M; mean skin temperature 34°C). Maximal LDF were obtained at the end of both protocols (50mM SNP). During heating RSR varied among sites (p<0.0001) and was greater on the back versus other sites (p<0.05), but LDF was similar between sites (p=0.343). RSR and SkBF showed a strong relation during initial (arm r=0.77±0.09, thigh r=0.81±0.08, abdomen r=0.89±0.04, back r=0.86±0.04) but not latter stages of heating. No differences in RSR (p=0.160) or SkBF (LDF, p=0.841) were observed between sites during ACh perfusion. Taken together, these data suggest that increases in SkBF are necessary to initiate and increase sweating, but further rises in RSR are not fully dependent on SkBF in a dose-response manner. Further, RSR cannot be explained by cholinergic sensitivity or variation in SkBF.
    AJP Regulatory Integrative and Comparative Physiology 02/2013; · 3.28 Impact Factor
  • Lacy M Alexander, Jessica L Kutz, W Larry Kenney
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    ABSTRACT: Localized R-BH(4) corrects the deficit in local heat-induced vasodilation (VD) in hypercholesterolemic (HC) human skin through one of two plausible mechanisms: by serving as an essential cofactor for eNOS or through generalized antioxidant effects. We used the S-BH(4), which has the same antioxidant properties but does not function as a NOS cofactor, to elucidate the mechanism by which R-BH(4) restores cutaneous VD in hypercholesterolemic humans. Intradermal microdialysis fibers were placed in 20 normocholesterolemic (NC), 13 mid-range cholesterolemic (MC) and 18 hypercholesterolemic (LDL: 94±3, 124±3 and 179±6 mg/dl, respectively) men and women to perfuse Ringers and R-BH(4). In 10 NC, 13 MC and 9 HC subjects (LDL: 94±3, 124±3, 180±10 mg/dl), S-BH(4) was perfused at a third site. Skin blood flow was measured during a local heating protocol to elicit eNOS-dependent VD. After cutaneous vascular conductance (CVC = LDF/ MAP) plateaued, NO-dependent VD was quantified (L-NAME). Data were normalized as %CVC(max). Fully-expressed VD (NC: 97.9±2.3 vs. MC: 85.4±5.4 & HC: 79.9±4.2%CVC(max)) and NO-dependent VD (NC: 62.1±3 vs. MC: 45.8±3.9 & HC: 35.7±2.8%CVC(max)) were reduced in HC (p<0.01 vs. NC), but only the fully expressed VD was reduced in MC (p<0.01 vs. NC). R-BH(4) increased the fully-expressed (93.9±3.4%CVC(max); p<0.01) and NO-dependent VD (52.1±5.1%CVC(max); p<0.01) in HC but not in NC or MC. S-BH(4) increased full-expressed VD in HC (p<0.01) but did not affect NO-dependent VD in HC or MC. In contrast S-BH(4) attenuated NO-dependent VD in NC (41.6±7%CVC(max); p<0.001). R-BH(4) restores NO-dependent VD in hypercholesterolemic human skin predominantly through NOS coupling mechanisms.
    AJP Regulatory Integrative and Comparative Physiology 11/2012; · 3.28 Impact Factor
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    ABSTRACT: Antithrombotic therapy with oral aspirin or clopidogrel (Plavix®) is associated with an attenuated skin vasodilator response and a greater rate of rise in core temperature in healthy, middle-aged individuals during passive heating in a water perfused suit. PURPOSE: The present double-blind, crossover study examined the functional consequences of 7 days of low-dose aspirin (ASA, 81 mg/day) vs.clopidogrel (CLO, 75 mg/day) treatment in 14 healthy, middle-aged (50-65 yrs) men and women during passive heating in air (40 min at 30°C, 40% rh) followed by exercise (60% O2peak). METHODS: Oral temperature (Tor) was measured in the antechamber (23.0 ± 0.1°C) before entering a warm environmental chamber. After 40 minutes of rest subjects cycled on a recumbent cycle ergometer for up to 120 minutes. Esophageal temperature (Tes) and laser Doppler flux were measured continuously, and the latter was normalized to maximal cutaneous vascular conductance (%CVCmax). RESULTS: Prior to entry into the environmental chamber there were no differences in Tor among treatments; however, after 40 minutes of rest in the heat, Tes was significantly higher for ASA and CLO vs. placebo (37.2±0.1°C, 37.3±0.1°C, vs. 37.0±0.1°C, both P<0.001), a difference that persisted throughout exercise (P<0.001 vs. placebo). The mean body temperature thresholds for the onset of cutaneous vasodilation were shifted to the right for both ASA and CLO during exercise (P<0.05). CONCLUSION: ASA and CLO resulted in elevated core temperatures during passive heat stress and shifted the onset of peripheral thermoeffector mechanisms toward higher body temperatures during exercise heat stress.
    Medicine and science in sports and exercise 11/2012; · 3.71 Impact Factor
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    ABSTRACT: The human cutaneous circulation is an accessible and representative regional circulation for investigating mechanisms of microvascular dysfunction, a systemic disease process occurring early in the pathogenesis of atherosclerosis. Elevated concentrations of low-density lipoproteins ([LDL]) are highly atherogenic and independently associated with the severity of coronary atherosclerosis through their actions on the lectin-like oxidized LDL receptors (LOX-1). We hypothesized that cutaneous microvascular dysfunction, as measured by a decrement in endothelial nitric oxide- (NO-) dependent vasodilation during local heating, would be correlated with serum [LDL], oxidized [LDL], and soluble LOX-1 receptors [sLOX-1]. Intradermal microdialysis fibers were placed in the skin of 53 otherwise healthy men and women (aged 52±8yrs) whose serum [LDL] ranged from 72 to 233mg/dL. Skin blood flow was measured by laser Doppler flowmetry over a local forearm skin site as it was heated (42°C) to induce sustained local vasodilation. After flux plateaued, L-NAME was infused to block endothelial NO synthase in order to determine the NO-dependent portion of the vasodilatory response. Data were normalized to maximal cutaneous vascular conductance (CVC). NO-dependent vasodilation was reduced as a linear function of [LDL] (R(2)=0.303, p<0.001), oxidized [LDL] (R(2)=0.214, p<0.001), and [sLOX-1] (R(2)=0.259, p=0.026) but was unrelated to high-density lipoprotein (HDL) concentration (R(2)=0.003, p=0.68). Hypercholesterolemia-induced microvascular dysfunction is related to various LDL markers and involves a reduction in NO-dependent vasodilation that appears to be a progressive process measurable in the skin microcirculation.
    Microvascular Research 11/2012; · 2.93 Impact Factor
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    ABSTRACT: Local skin heating is used to assess microvascular function in clinical populations because NO is required for full expression of the response; however, controversy exists as to the precise NO synthase (NOS) isoform producing NO. Human aging is associated with attenuated cutaneous vasodilation but little is known about the middle aged, an age cohort used for comparison with clinical populations. We hypothesized that endothelial NOS (eNOS) is the primary isoform mediating NO production during local heating, and eNOS-dependent vasodilation would be reduced in middle-aged skin. Vasodilation was induced by local heating (42°C) and during acetylcholine dose-response (ACh-DR: 0.01, 0.1, 1.0, 5.0, 10.0, 50.0, 100.0 mmol/l) protocols. Four microdialysis fibers were placed in the skin of 24 men and women; age cohorts were 12 middle-aged (53 ± 1 yr) and 12 young (23 ± 1 yr). Sites served as control, nonselective NOS inhibited [N(G)-nitro-l-arginine methyl ester (l-NAME)], inducible NOS (iNOS) inhibited (1400W), and neuronal NOS (nNOS) inhibited (N(ω)-propyl-l-arginine). After full expression of the local heating response, l-NAME was perfused at all sites. Cutaneous vascular conductance was measured and normalized to maximum (%CVC(max): Nitropress). l-NAME reduced %CVCmax at baseline, all phases of the local heating response, and at all ACh concentrations compared with all other sites. iNOS inhibition reduced the initial peak (53 ± 2 vs. 60 ± 2%CVC(max); P < 0.001); however, there were no other differences between control, nNOS-, and iNOS-inhibited sites during the phases of local heating or ACh-DR. When age cohorts were compared, NO-dependent vasodilation during local heating (52 ± 6 vs. 68 ± 4%CVC(max); P = 0.013) and ACh perfusion (50 mmol/l: 83 ± 3 vs. 93 ± 2%CVC(max); 100 mmol/l: 83 ± 4 vs. 92 ± 3%CVC(max); both P = 0.03) were reduced in middle-aged skin. There were no differences in NOS isoform expression obtained from skin biopsy samples between groups (all P > 0.05). These data suggest that eNOS mediates the production of NO during local heating and that cutaneous vasodilation is attenuated in middle-aged skin.
    Journal of Applied Physiology 04/2012; 112(12):2019-26. · 3.48 Impact Factor
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    ABSTRACT: 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 (BH(4)) 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 BH(4) 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 BH(4), 3) 5 mM (S)-(2-boronoethyl)-l-cysteine + 5 mM N(ω)-hydroxy-nor-l-arginine to inhibit arginase, and 4) 20 mM N(G)-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 (T(or)), 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 (%CVC(max); 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 T(or). BH(4) and arginase inhibition both increased vasodilation in older (BH(4): 55 ± 5%; arginase-inhibited: 47 ± 5% vs. control: 37 ± 3%, both P < 0.01) but not young subjects compared with control (BH(4): 51 ± 4%CVC(max); arginase-inhibited: 55 ± 4%CVC(max) vs. control: 56 ± 6%CVC(max), both P > 0.05) at a 1°C rise in T(or). With a 1°C rise in T(or), local BH(4) increased NO-dependent vasodilation in the older (BH(4): 31.8 ± 2.4%CVC(max) vs. control: 11.7 ± 2.0%CVC(max), P < 0.001) but not the young (BH(4): 23 ± 4%CVC(max) vs. control: 21 ± 4%CVC(max), P = 0.718) subject group. Together these data suggest that reduced BH(4) contributes to attenuated vasodilation in aged human skin and that BH(4) NOS coupling mechanisms may be a potential therapeutic target for increasing skin blood flow during hyperthermia in older humans.
    Journal of Applied Physiology 12/2011; 112(5):791-7. · 3.48 Impact Factor
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    Lacy A Holowatz, W Larry Kenney
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    ABSTRACT: Elevated oxidized low-density lipoproteins (LDL) are associated with vascular dysfunction in the cutaneous microvasculature, induced in part by upregulated arginase activity and increased globalized oxidant stress. Since tetrahydrobiopterin (BH(4)) is an essential cofactor for endothelial nitric oxide synthase (NOS3), decreased bioavailability of the substrate l-arginine and/or BH(4) may contribute to decreased NO production with hypercholesterolaemia. We hypothesized that (1) localized administration of BH(4) would augment NO-dependent vasodilatation in hypercholesterolaemic human skin, which would be further increased when combined with arginase inhibition and (2) the improvement induced by localized BH(4) would be attenuated after a 3 month oral atorvastatin intervention (10 mg). Four microdialysis fibres were placed in the skin of nine normocholesterolaemic (NC: LDL = 95 ± 4 mg dl(-1)) and nine hypercholesterolaemic (HC: LDL = 177 ± 6 mg dl(-1)) men and women before and after 3 months of systemic atorvastatin. Sites served as control, NOS inhibited, BH(4), and arginase inhibited + BH(4) (combo). Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilatation. After the established plateau l-NAME was perfused in all sites to quantify NO-dependent vasodilatation (NO). Data were normalized to maximum cutaneous vascular conductance (CVC). Vasodilatation at the plateau and NO-dependent vasodilatation were reduced in HC subjects (plateau HC: 70 ± 5% CVC(max) vs. NC: 95 ± 2% CVC(max); NO HC: 45 ± 5% CVC(max) vs. NC: 64 ± 5% CVC(max); both P < 0.001). Localized BH(4) alone or combo augmented the plateau (BH(4): 93 ± 3% CVC(max); combo 89 ± 3% CVC(max), both P < 0.001) and NO-dependent vasodilatation in HC (BH(4): 74 ± 3% CVC(max); combo 76 ± 3% CVC(max), both P < 0.001), but there was no effect in NC subjects (plateau BH(4): 90 ± 2% CVC(max); combo 95 ± 3% CVC(max); NO-dependent vasodilatation BH(4): 68 ± 3% CVC(max); combo 58 ± 4% CVC(max), all P > 0.05 vs. control site). After the atorvastatin intervention (LDL = 98 ± mg * dl(-1)) there was an increase in the plateau in HC (96 ± 4% CVC(max), P < 0.001) and NO-dependent vasodilatation (68 ± 3% CVC(max), P < 0.001). Localized BH(4) alone or combo was less effective at increasing NO-dependent vasodilatation after the drug intervention (BH(4): 60 ± 5% CVC(max); combo 58 ± 2% CVC(max), both P < 0.001). These data suggest that decreased BH(4) bioavailability contributes in part to cutaneous microvascular dysfunction in hypercholesterolaemic humans and that atorvastatin is an effective systemic treatment for improving NOS coupling mechanisms in the microvasculature.
    The Journal of Physiology 08/2011; 589(Pt 19):4787-97. · 4.38 Impact Factor
  • Lacy A Holowatz, W Larry Kenney
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    ABSTRACT: Elevated low-density lipoproteins (LDL) are associated with cutaneous microvascular dysfunction partially mediated by increased arginase activity, which is decreased following a systemic atorvastatin therapy. We hypothesized that increased ascorbate-sensitive oxidant stress, partially mediated through uncoupled nitric oxide synthase (NOS) induced by upregulated arginase, contributes to cutaneous microvascular dysfunction in hypercholesterolemic (HC) humans. Four microdialysis fibers were placed in the skin of nine HC (LDL = 177 ± 6 mg/dl) men and women before and after 3 mo of a systemic atorvastatin intervention and at baseline in nine normocholesterolemic (NC) (LDL = 95 ± 4 mg/dl) subjects. Sites served as control, NOS inhibited, L-ascorbate, and arginase-inhibited+L-ascorbate. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilation. After the established plateau in all sites, 20 mM ≪ngname≫ was infused to quantify NO-dependent vasodilation. Data were normalized to maximum cutaneous vascular conductance (CVC) (sodium nitroprusside + 43°C). The plateau in vasodilation during local heating (HC: 78 ± 4 vs. NC: 96 ± 2% CVC(max), P < 0.01) and NO-dependent vasodilation (HC: 40 ± 4 vs. NC: 54 ± 4% CVC(max), P < 0.01) was reduced in the HC group. Acute L-ascorbate alone (91 ± 5% CVC(max), P < 0.001) or combined with arginase inhibition (96 ± 3% CVC(max), P < 0.001) augmented the plateau in vasodilation in the HC group but not the NC group (ascorbate: 96 ± 2; combo: 93 ± 4% CVC(max), both P > 0.05). After the atorvastatin intervention NO-dependent vasodilation was augmented in the HC group (HC postatorvastatin: 64 ± 4% CVC(max), P < 0.01), and there was no further effect of ascorbate alone (58 ± 4% CVC(max,) P > 0.05) or combined with arginase inhibition (67 ± 4% CVC(max,) P > 0.05). Increased ascorbate-sensitive oxidants contribute to hypercholesteromic associated cutaneous microvascular dysfunction which is partially reversed with atorvastatin therapy.
    AJP Regulatory Integrative and Comparative Physiology 06/2011; 301(3):R763-8. · 3.28 Impact Factor
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    ABSTRACT: Heat is the most abundant byproduct of cellular metabolism. As such, dynamic exercise in which a significant percentage of muscle mass is engaged generates thermoregulatory demands that are met in part by increases in skin blood flow. Increased skin blood flow during exercise adds to the demands on cardiac output and confers additional circulatory strain beyond that associated with perfusion of active muscle alone. Endurance exercise training results in a number of physiological adaptations which ultimately reduce circulatory strain and shift thermoregulatory control of skin blood flow to higher levels of blood flow for a given core temperature. In addition, exercise training induces peripheral vascular adaptations within the cutaneous microvasculature indicative of enhanced endothelium-dependent vasomotor function. However, it is not currently clear how (or if) these local vascular adaptations contribute to the beneficial changes in thermoregulatory control of skin blood flow following exercise training. The purpose of this Hot Topic Review is to synthesize the literature pertaining to exercise training-mediated changes in cutaneous microvascular reactivity and thermoregulatory control of skin blood flow. In addition, we address mechanisms driving changes in cutaneous microvascular reactivity and thermoregulatory control of skin blood flow, and pose the question: what (if any) is the functional role of increased cutaneous microvascular reactivity following exercise training?
    Experimental physiology 05/2011; 96(9):822-8. · 3.17 Impact Factor
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    ABSTRACT: Elevated low-density lipoproteins (LDLs) are associated with vascular dysfunction evident in the cutaneous microvasculature. We hypothesized that uncoupled endothelial nitric oxide synthase (NOS3) through upregulated arginase contributes to cutaneous microvascular dysfunction in hyperocholesterolaemic (HC) humans and that a statin intervention would decrease arginase activity. Five microdialysis fibres were placed in the skin of nine normocholesterolaemic (NC: LDL level 95±4 mg dl⁻¹) and nine hypercholesterolaemic (HC: LDL: 177±6 mg dl⁻¹) men and women before and after 3 months of systemic atrovastatin. Sites served as control, NOS inhibited, arginase inhibited, L-arginine supplemented and arginase inhibited plus L-arginine supplemented. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilatation. L-NAME was infused after the established plateau in all sites to quantify NO-dependent vasodilatation. Data were normalized to maximum cutaneous vascular conductance (CVC(max)). Skin samples were obtained to measure total arginase activity and arginase I and arginase II protein. Vasodilatation was reduced in hyperocholesterolaemic subjects (HC: 76±2 vs. NC: 94±3%CVC(max), P < 0.001) as was NO-dependent vasodilatation (HC: 43±5 vs. NC: 62±4%CVC(max), P < 0.001). The plateau and NO-dependent vasodilatation were augmented in HC with arginase inhibition (92±2, 67±2%CVC(max), P < 0.001), L-arginine (93±2, 71±5%CVC(max), P < 0.001) and combined treatments (94±4, 65±5%CVC(max), P < 0.001) but not in NC. After statin intervention (LDL: 98±5 mg dl⁻¹) there was no longer a difference between control sites (88±4, 61±5%CVC(max)) and localized microdialysis treatment sites (all P > 0.05). Arginase activity and protein were increased in HC skin (P < 0.05 vs. NC) and activity decreased with atrovastatin treatment (P < 0.05). Reduced NOS3 substrate availability through upregulated arginase contributes to cutaneous microvascular dysfunction in hyperocholesterolaemic humans, which is corrected with atorvastatin therapy.
    The Journal of Physiology 04/2011; 589(Pt 8):2093-103. · 4.38 Impact Factor
  • James A Lang, Lacy A Holowatz, W Larry Kenney
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    ABSTRACT: We have recently demonstrated that tetrahydrobiopterin (BH(4)) augments reflex vasoconstriction (VC) in aged skin. Although this appears to occur through its role in norepinephrine (NE) biosynthesis, the extent with which vascular mechanisms are affected are unknown. We hypothesized that localized BH(4) supplementation would not affect the VC response to exogenous NE when sympathetic nerves were blocked. Two microdialysis fibers were placed in bretylium tosylate pretreated (presynaptically blocks neurotransmitter release from sympathetic adrenergic nerve terminals; iontophoresis, 200 μA for 20 min) 3-cm(2) forearm skin of 10 young (Y) and 10 older (O) subjects for perfusion of 1) Ringer (control) and 2) 5 mM BH(4). While local skin temperature was clamped at 34°C, six concentrations of NE (10(-12), 10(-10), 10(-8), 10(-6), 10(-4), 10(-2) M) were infused at each drug-treated site. Cutaneous vascular conductance (CVC) was calculated (CVC = laser Doppler flux/mean arterial pressure) and normalized to baseline (%ΔCVC(base)). Despite prejunctional adrenergic blockade, NE-mediated VC was blunted in aged skin at each NE dose (10(-12): -12 ± 2 vs. -21 ± 2; 10(-10): -15 ± 2 vs. -27 ± 1; 10(-8): -22 ± 2 vs. -32 ± 2; 10(-6): -27 ± 2 vs. -38 ± 1; 10(-4): -52 ± 3 vs. -66 ± 5; 10(-2): -62 ± 3 vs. -75 ± 4%ΔCVC(base); P < 0.01), and this response was not affected by pretreatment with BH(4) (P > 0.05). Localized BH(4) did not affect end-organ responsiveness to exogenous NE, suggesting that the effects of BH(4) on cutaneous VC are primarily isolated to the NE biosynthetic pathway.
    AJP Regulatory Integrative and Comparative Physiology 10/2010; 299(6):R1651-5. · 3.28 Impact Factor
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    ABSTRACT: 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 degrees 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 degrees C). During ND conditions, SkBF with change (Delta) in Tor=1.0 degrees 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 degrees 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.
    Journal of Applied Physiology 04/2010; 108(6):1575-81. · 3.48 Impact Factor
  • Lacy A Holowatz, W Larry Kenney
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    ABSTRACT: Human skin blood flow is controlled via dual innervation from the sympathetic nervous system. Reflex cutaneous vasoconstriction and vasodilation are both impaired with primary aging, rendering the aged more vulnerable to hypothermia and cardiovascular complications from heat-related illness. Age-related alterations in the thermoregulatory control of skin blood flow occur at multiple points along the efferent arm of the reflex, including 1) diminished sympathetic outflow, 2) altered presynaptic neurotransmitter synthesis, 3) reduced vascular responsiveness, and 4) impairments in downstream (endothelial and vascular smooth muscle) second-messenger signaling. This mechanistic review highlights some of the recent findings in the area of aging and the thermoregulatory control of skin blood flow.
    Journal of Applied Physiology 04/2010; 109(5):1538-44. · 3.48 Impact Factor

Publication Stats

2k Citations
394.15 Total Impact Points

Institutions

  • 1985–2013
    • Pennsylvania State University
      • Department of Kinesiology
      State College, PA, United States
  • 2011
    • University of Missouri
      • Department of Biomedical Sciences
      Columbia, MO, United States
  • 2010
    • The Children's Hospital of Philadelphia
      • Department of Pediatrics
      Philadelphia, PA, United States
  • 2009
    • Park University
      Parkville, Missouri, United States
  • 2008
    • Johns Hopkins University
      • Department of Biomedical Engineering
      Baltimore, MD, United States
    • U.S. Army Research Institute of Environmental Medicine
      Natick, Massachusetts, United States
  • 1999
    • Osaka International University for Women
      Ōsaka, Ōsaka, Japan
  • 1994
    • University of South Florida
      • College of Public Health
      Tampa, FL, United States