scholarly journals Acute ultraviolet radiation exposure attenuates nitric oxide-mediated vasodilation in the cutaneous microvasculature of healthy humans

2018 ◽  
Vol 125 (4) ◽  
pp. 1232-1237 ◽  
Author(s):  
S. Tony Wolf ◽  
Anna E. Stanhewicz ◽  
Nina G. Jablonski ◽  
W. Larry Kenney
Keyword(s):  
Nitric Oxide ◽  
Radiation Exposure ◽  
Local Heating ◽  
Skin Pigmentation ◽  
Ultraviolet B ◽  
Uvb Radiation ◽  
Doppler Flowmetry ◽  
Healthy Humans ◽  
Cutaneous Vasodilation ◽  
Uvb Exposure

5-Methyltetrahydrofolate (5-MTHF) is important for nitric oxide (NO)-mediated cutaneous microvascular vasodilation. Ultraviolet B (UVB) radiation may deplete 5-MTHF, either directly or via production of reactive oxygen species (ROS), decreasing NO-mediated vasodilation. We hypothesized that 1) acute UVB exposure would attenuate NO-dependent cutaneous vasodilation, 2) local perfusion of 5-MTHF or ascorbate (ASC) (antioxidant) would augment NO-dependent vasodilation after UVB, and 3) darker skin pigmentation would be UVB-protective. Intradermal microdialysis fibers ( n = 3) placed in each forearm of 22 healthy young adults (23 ± 1 yr; 8M/14F) locally delivered lactated Ringer’s (control), 5 mM 5-MTHF, or 10 mM ASC. One arm was UVB-exposed (300 mJ/cm2), and the other served as a nonexposed control (CON). Following UVB exposure, a standardized local heating (42°C) protocol induced cutaneous vasodilation. After attaining a plateau blood flow, 15 mM NG-nitro-l-arginine methyl ester (nitric oxide synthase inhibiter) was infused at all sites to quantify the NO contribution. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC = LDF/mean arterial pressure) was expressed as a percentage of maximum (28 mM sodium nitroprusside + 43°C). UVB attenuated NO-mediated vasodilation compared with CON (23.1 ± 3.6 vs. 33.9 ± 3.4%; P = 0.001). Delivery of 5-MTHF or ASC improved NO-mediated vasodilation versus lactated Ringer’s in the UVB-exposed arm (MTHF: 30.1 ± 4.8% vs. 23.1 ± 3.8%; P = 0.03; ASC: 30.9 ± 4.3% vs. 23.1 ± 3.8%; P = 0.02). Neither treatment affected the response in the nonexposed arm ( P ≥ 0.09). Skin pigmentation (melanin index) was not predictive of the UVB response ( P ≥ 0.34). These data suggest that acute UVB exposure attenuates NO-mediated vasodilation via direct and/or ROS-induced reductions in 5-MTHF, independent of skin pigmentation. NEW & NOTEWORTHY Endothelial-derived nitric oxide (NO) contributes to normal healthy function of the human cutaneous microvasculature. Bioavailability of 5-methyltetrahydrofolate (5-MTHF) is important for the production of NO. Ultraviolet (UV) radiation exposure, specifically UVB, may deplete cutaneous 5-MTHF, thereby reducing NO-mediated microvascular function. Our findings suggest that acute UVB exposure attenuates NO-mediated vasodilation of the cutaneous microvasculature via degradation of 5-MTHF. These findings advance our understanding of the potential negative health impacts of acute UV exposure.

Decreased nitric oxide- and axon reflex-mediated cutaneous vasodilation with age during local heating

2002 ◽  
Vol 93 (5) ◽  
pp. 1644-1649 ◽  
Author(s):  
Christopher T. Minson ◽  
Lacy A. Holowatz ◽  
Brett J. Wong ◽  
W. Larry Kenney ◽  
Brad W. Wilkins
Keyword(s):  
Nitric Oxide ◽  
Local Heating ◽  
The Elderly ◽  
Axon Reflex ◽  
Doppler Flowmetry ◽  
Cutaneous Vasodilation ◽  
Age Related ◽  
Older Subjects ◽  
Initial Peak ◽  
Age Related Changes

Cutaneous vasodilation is reduced in healthy older vs. young subjects; however, the mechanisms that underlie these age-related changes are unclear. Our goal in the present study was to determine the role of nitric oxide (NO) and the axon reflexes in the skin blood flow (SkBF) response to local heating with advanced age. We placed two microdialysis fibers in the forearm skin of 10 young (Y; 22 ± 2 yr) and 10 older (O; 77 ± 5 yr) men and women. SkBF over each site was measured by laser-Doppler flowmetry (LDF; Moor DRT4). Both sites were heated to 42°C for ∼60 min while 10 mM N G-nitro-l-arginine methyl ester (l-NAME) was infused throughout the protocol to inhibit NO synthase (NOS) in one site and 10 mM l-NAME was infused after 40 min of local heating in the second site. Data were expressed as a percentage of maximal vasodilation (%CVCmax; 28 mM nitroprusside infusion). Local heating beforel-NAME infusion resulted in a significantly reduced initial peak (Y: 61 ± 2%CVCmax vs. O: 46 ± 4%CVCmax) and plateau (Y: 93 ± 2%CVCmaxvs. O: 82 ± 5%CVCmax) CVC values in older subjects ( P < 0.05). When NOS was inhibited after 40 min of heating, CVC declined to the same value in the young and older groups. Thus the overall contribution of NO to the plateau phase of the SkBF response to local heating was less in the older subjects. The initial peak response was significantly lower in the older subjects in both microdialysis sites (Y: 52 ± 4%CVCmax vs. O: 38 ± 5%CVCmax; P < 0.05). These data suggest that age-related changes in both axon reflex-mediated and NO-mediated vasodilation contribute to attenuated cutaneous vasodilator responses in the elderly.

Preserved reflex cutaneous vasodilation in cystic fibrosis does not include an enhanced nitric oxide-dependent mechanism

2007 ◽  
Vol 102 (6) ◽  
pp. 2301-2306 ◽  
Author(s):  
Brad W. Wilkins ◽  
Elizabeth A. Martin ◽  
Shelly K. Roberts ◽  
Michael J. Joyner
Keyword(s):  
Nitric Oxide ◽  
Cystic Fibrosis ◽  
Blood Flow ◽  
Skin Blood Flow ◽  
Local Heating ◽  
No Synthase ◽  
Local Skin ◽  
Doppler Flowmetry ◽  
Cutaneous Vasodilation ◽  
Reflex Cutaneous Vasodilation

In humans, vasoactive intestinal peptide (VIP) may play a role in reflex cutaneous vasodilation during body heating. We tested the hypothesis that the nitric oxide (NO)-dependent contribution to active vasodilation is enhanced in the skin of subjects with cystic fibrosis (CF), compensating for sparse levels of VIP. In 2 parallel protocols, microdialysis fibers were placed in the skin of 11 subjects with CF and 12 controls. Lactated Ringer was perfused at one microdialysis site and NG-nitro-l-arginine methyl ester (2.7 mg/ml) was perfused at a second microdialysis site. Skin blood flow was monitored over each site with laser-Doppler flowmetry. In protocol 1, local skin temperature was increased 0.5°C every 5 s to 42°C, and then it maintained at 42°C for ∼45 min. In protocol 2, subjects wore a tube-lined suit perfused with water at 50°C, sufficient to increase oral temperature (Tor) 0.8°C. Cutaneous vascular conductance (CVC) was calculated (flux/mean arterial pressure) and scaled as percent maximal CVC (sodium nitroprusside; 8.3 mg/ml). Vasodilation to local heating was similar between groups. The change (Δ%CVCmax) in CVC with NO synthase inhibition on the peak (9 ± 3 vs. 12 ± 5%CVCmax; P = 0.6) and the plateau (45 ± 3 vs. 35 ± 5%CVCmax; P = 0.1) phase of the skin blood flow response to local heating was similar in CF subjects and controls, respectively. Reflex cutaneous vasodilation increased CVC in CF subjects (58 ± 4%CVCmax) and controls (53 ± 4%CVCmax; P = 0.37) and NO synthase inhibition attenuated CVC in subjects with CF (37 ± 6%CVCmax) and controls (35 ± 5%CVCmax; P = 0.8) to a similar degree. Thus the preservation of cutaneous active vasodilation in subjects with CF is not associated with an enhanced NO-dependent vasodilation.

scholarly journals Oral atorvastatin therapy increases nitric oxide-dependent cutaneous vasodilation in humans by decreasing ascorbate-sensitive oxidants

2011 ◽  
Vol 301 (3) ◽  
pp. R763-R768 ◽  
Author(s):  
Lacy A. Holowatz ◽  
W. Larry Kenney
Keyword(s):  
Nitric Oxide ◽  
Local Heating ◽  
Oxidant Stress ◽  
Microvascular Dysfunction ◽  
Local Skin ◽  
Cutaneous Vasodilation ◽  
Before And After ◽  
Atorvastatin Therapy ◽  
Oxide Synthase ◽  
Cutaneous Vascular Conductance

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% CVCmax, P < 0.01) and NO-dependent vasodilation (HC: 40 ± 4 vs. NC: 54 ± 4% CVCmax, P < 0.01) was reduced in the HC group. Acute L-ascorbate alone (91 ± 5% CVCmax, P < 0.001) or combined with arginase inhibition (96 ± 3% CVCmax, P < 0.001) augmented the plateau in vasodilation in the HC group but not the NC group (ascorbate: 96 ± 2; combo: 93 ± 4% CVCmax, both P > 0.05). After the atorvastatin intervention NO-dependent vasodilation was augmented in the HC group (HC postatorvastatin: 64 ± 4% CVCmax, P < 0.01), and there was no further effect of ascorbate alone (58 ± 4% CVCmax, P > 0.05) or combined with arginase inhibition (67 ± 4% CVCmax, P > 0.05). Increased ascorbate-sensitive oxidants contribute to hypercholesteromic associated cutaneous microvascular dysfunction which is partially reversed with atorvastatin therapy.

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

2009 ◽  
Vol 106 (2) ◽  
pp. 500-505 ◽  
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.

Nitric oxide and attenuated reflex cutaneous vasodilation in aged skin

2003 ◽  
Vol 284 (5) ◽  
pp. H1662-H1667 ◽  
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.

scholarly journals Roles of nitric oxide synthase isoforms in cutaneous vasodilation induced by local warming of the skin and whole body heat stress in humans

2009 ◽  
Vol 107 (5) ◽  
pp. 1438-1444 ◽  
Author(s):  
Dean L. Kellogg ◽  
Joan L. Zhao ◽  
Yubo Wu
Keyword(s):  
Nitric Oxide ◽  
Heat Stress ◽  
No Synthase ◽  
Whole Body ◽  
Doppler Flowmetry ◽  
Vasodilator Response ◽  
Cutaneous Vasodilation ◽  
Forearm Skin ◽  
Whole Body Heat Stress ◽  
Body Heat

Nitric oxide (NO) participates in the cutaneous vasodilation caused by increased local skin temperature (Tloc) and whole body heat stress in humans. In forearm skin, endothelial NO synthase (eNOS) participates in vasodilation due to elevated Tloc and neuronal NO synthase (nNOS) participates in vasodilation due to heat stress. To explore the relative roles and interactions of these isoforms, we examined the effects of a relatively specific eNOS inhibitor, Nω-amino-l-arginine (LNAA), and a specific nNOS inhibitor, Nω-propyl-l-arginine (NPLA), both separately and in combination, on skin blood flow (SkBF) responses to increased Tloc and heat stress in two protocols. In each protocol, SkBF was monitored by laser-Doppler flowmetry (LDF) and mean arterial pressure (MAP) by Finapres. Cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). Intradermal microdialysis was used to treat one site with 5 mM LNAA, another with 5 mM NPLA, a third with combined 5 mM LNAA and 5 mM NPLA (Mix), and a fourth site with Ringer only. In protocol 1, Tloc was controlled with combined LDF/local heating units. Tloc was increased from 34°C to 41.5°C to cause local vasodilation. In protocol 2, after a period of normothermia, whole body heat stress was induced (water-perfused suits). At the end of each protocol, all sites were perfused with 58 mM nitroprusside to effect maximal vasodilation for data normalization. In protocol 1, at Tloc = 34°C, CVC did not differ between sites ( P > 0.05). LNAA and Mix attenuated CVC increases at Tloc = 41.5°C to similar extents ( P < 0.05, LNAA or Mix vs. untreated or NPLA). In protocol 2, in normothermia, CVC did not differ between sites ( P > 0.05). During heat stress, NPLA and Mix attenuated CVC increases to similar extents, but no significant attenuation occurred with LNAA ( P < 0.05, NPLA or Mix vs. untreated or LNAA). In forearm skin, eNOS mediates the vasodilator response to increased Tloc and nNOS mediates the vasodilator response to heat stress. The two isoforms do not appear to interact during either response.

scholarly journals Blunted increases in skin sympathetic nerve activity are related to attenuated reflex vasodilation in aged human skin

2016 ◽  
Vol 121 (6) ◽  
pp. 1354-1362 ◽  
Author(s):  
Anna E. Stanhewicz ◽  
Jody L. Greaney ◽  
Lacy M. Alexander ◽  
W. Larry Kenney
Keyword(s):  
Older Adults ◽  
Sympathetic Nerve Activity ◽  
Local Heating ◽  
Doppler Flowmetry ◽  
Healthy Older Adults ◽  
Cutaneous Vasodilation ◽  
Age Related ◽  
Dorsum Of Foot ◽  
Reflex Cutaneous Vasodilation ◽  
Cutaneous Vascular Conductance

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.

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

2012 ◽  
Vol 112 (5) ◽  
pp. 791-797 ◽  
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.

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

2007 ◽  
Vol 293 (2) ◽  
pp. H1090-H1096 ◽  
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.

scholarly journals Endothelial nitric oxide synthase control mechanisms in the cutaneous vasculature of humans in vivo

2008 ◽  
Vol 295 (1) ◽  
pp. H123-H129 ◽  
Author(s):  
Dean L. Kellogg ◽  
Joan L. Zhao ◽  
Yubo Wu
Keyword(s):  
Nitric Oxide ◽  
Heat Stress ◽  
Local Heating ◽  
Ringer Solution ◽  
Whole Body ◽  
Control Mechanisms ◽  
Local Skin ◽  
Doppler Flowmetry ◽  
Whole Body Heat Stress ◽  
Body Heat

Nitric oxide (NO) participates in locally mediated vasodilation induced by increased local skin temperature (Tloc) and in sympathetically mediated vasodilation during whole body heat stress. We hypothesized that endothelial NOS (eNOS) participates in the former, but not the latter, response. We tested this hypothesis by examining the effects of the eNOS antagonist NG-amino-l-arginine (l-NAA) on skin blood flow (SkBF) responses to increased Tloc and whole body heat stress. Microdialysis probes were inserted into forearm skin for drug delivery. One microdialysis site was perfused with l-NAA in Ringer solution and a second site with Ringer solution alone. SkBF [laser-Doppler flowmetry (LDF)] and blood pressure [mean arterial pressure (MAP)] were monitored, and cutaneous vascular conductance (CVC) was calculated (CVC = LDF ÷ MAP). In protocol 1, Tloc was controlled with LDF/local heating units. Tloc initially was held at 34°C and then increased to 41.5°C. In protocol 2, after a normothermic period, whole body heat stress was induced (water-perfused suits). At the end of both protocols, 58 mM sodium nitroprusside was perfused at both microdialysis sites to cause maximal vasodilation for data normalization. In protocol 1, CVC at 34°C Tloc did not differ between l-NAA-treated and untreated sites ( P > 0.05). Local skin warming to 41.5°C Tloc increased CVC at both sites. This response was attenuated at l-NAA-treated sites ( P < 0.05). In protocol 2, during normothermia, CVC did not differ between l-NAA-treated and untreated sites ( P > 0.05). During heat stress, CVC rose to similar levels at l-NAA-treated and untreated sites ( P > 0.05). We conclude that eNOS is predominantly responsible for NO generation in skin during responses to increased Tloc, but not during reflex responses to whole body heat stress.

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