scholarly journals Tetrahydrobiopterin increases NO-dependent vasodilation in hypercholesterolemic human skin through eNOS-coupling mechanisms

2013 ◽  
Vol 304 (2) ◽  
pp. R164-R169 ◽  
Author(s):  
Lacy M. Alexander ◽  
Jessica L. Kutz ◽  
W. Larry Kenney
Keyword(s):  
Human Skin ◽  
Local Heating ◽  
Antioxidant Properties ◽  
Local Heat ◽  
Control Site ◽  
No Synthase ◽  
Endothelial Nitric Oxide ◽  
Coupling Mechanisms ◽  
Cutaneous Vascular Conductance ◽  
Antioxidant Effects

Localized exogenous R-tetrahydrobiopterin (R-BH4) 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 to stabilizing endothelial nitric oxide (NO) synthase (eNOS) or through generalized antioxidant effects. We used the stereoisomer S-BH4, which has the same antioxidant properties but does not function as an essential NOS cofactor, to elucidate the mechanism by which R-BH4 restores cutaneous VD in HC humans. Intradermal microdialysis fibers were placed in 20 normocholesterolemic (NC), 13 midrange cholesterolemic (MC), and 18 HC (LDL: 94 ± 3, 124 ± 3 and 179 ± 6 mg/dl, respectively) men and women to perfuse Ringer (control site) and R-BH4. In 10 NC, 13 MC, and 9 HC subjects (LDL: 94 ± 3, 124 ± 3, 180 ± 10 mg/dl), S-BH4 was perfused at a third microdialysis site. Skin blood flow was measured during a standardized local heating protocol to elicit eNOS-dependent VD. After cutaneous vascular conductance (CVC = LDF/MAP) plateaued, NO-dependent VD was quantified by perfusing NG-nitro-l-arginine methyl ester (l-NAME). Data were normalized as %CVCmax. Fully expressed VD (NC: 97.9 ± 2.3 vs. MC: 85.4 ± 5.4, HC: 79.9 ± 4.2%CVCmax) and the NO-dependent portion (NC: 62.1 ± 3 vs. MC: 45.8 ± 3.9, HC: 35.7 ± 2.8%CVCmax) were reduced in HC (both P < 0.01 vs. NC), but only the fully expressed VD was reduced in MC ( P < 0.01 vs. NC). R-BH4 increased the fully expressed (93.9 ± 3.4%CVCmax; P < 0.01) and NO-dependent VD (52.1 ± 5.1%CVCmax; P < 0.01) in HC but not in NC or MC. S-BH4 increased full-expressed VD in HC ( P < 0.01) but did not affect NO-dependent VD in HC or MC. In contrast S-BH4 attenuated NO-dependent VD in NC (control: 62.1 ± 3 vs. S-BH4: 41.6 ± 7%CVCmax; P < 0.001). Exogenous R-BH4 restores NO-dependent VD in HC human skin predominantly through NOS coupling mechanisms but increases full expression of the local heating response through generalized antioxidant properties.

scholarly journals Geldanamycin attenuates NO-mediated dilation in human skin

2002 ◽  
Vol 282 (1) ◽  
pp. H232-H236 ◽  
Author(s):  
Shubha Shastry ◽  
Michael J. Joyner
Keyword(s):  
Human Skin ◽  
Potential Role ◽  
Local Heating ◽  
Specific Inhibitor ◽  
Heat Shock Protein 90 ◽  
No Synthase ◽  
Vascular Conductance ◽  
Endothelial Nitric Oxide ◽  
Cutaneous Vascular Conductance ◽  
Cutaneous Blood

The binding of heat shock protein 90 (HSP90) to endothelial nitric oxide (NO) synthase (eNOS) can enhance eNOS activation. Studies have shown that the HSP90-specific inhibitor geldanamycin (GA) can cause attenuation of NO-mediated processes. Twenty subjects participated in one of two protocols. In each protocol, one forearm of each subject was instrumented with two intradermal microdialysis probes for drug delivery. Laser Doppler flowmeters were used to measure cutaneous blood flow. Skin sites were either treated with the endothelial agonist acetylcholine or locally heated to 42°C, a maneuver that evokes NO-mediated dilation. Interventions were performed with and without GA. In the presence of GA, maximal cutaneous vascular conductance (CVC) to ACh was 20 ± 3% lower than with ACh alone ( P < 0.001). During local heating, maximal CVC in the presence of GA was 22 ± 6% lower than during heating alone ( P < 0.01). The results show that GA can attenuate NO-mediated dilation in human skin, suggesting a potential role for HSP90 in activation of eNOS in the microcirculation.

Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin

2005 ◽  
Vol 98 (2) ◽  
pp. 629-632 ◽  
Author(s):  
D. L. Kellogg ◽  
J. L. Zhao ◽  
U. Coey ◽  
J. V. Green
Keyword(s):  
Nitric Oxide ◽  
Human Skin ◽  
Control Site ◽  
Relative Increase ◽  
No Synthase ◽  
Vascular Conductance ◽  
Doppler Flowmetry ◽  
Endothelial Nitric Oxide ◽  
Cutaneous Vascular Conductance ◽  
Cutaneous Blood

Acetylcholine (ACh) can effect vasodilation by several mechanisms, including activation of endothelial nitric oxide (NO) synthase and prostaglandin (PG) production. In human skin, exogenous ACh increases both skin blood flow (SkBF) and bioavailable NO levels, but the relative increase is much greater in SkBF than NO. This led us to speculate ACh may dilate cutaneous blood vessels through PGs, as well as NO. To test this hypothesis, we performed a study in 11 healthy people. We measured SkBF by laser-Doppler flowmetry (LDF) at four skin sites instrumented for intradermal microdialysis. One site was treated with ketorolac (Keto), a nonselective cyclooxygenase antagonist. A second site was treated with NG-nitro-l-arginine methyl ester (l-NAME) to inhibit NO synthase. A third site was treated with a combination of Keto and l-NAME. The fourth site was an untreated control site. After the three treated sites received the different inhibiting agents, ACh was administered to all four sites by intradermal microdialysis. Finally, sodium nitroprusside (SNP) was administered to all four sites. Mean arterial pressure (MAP) was monitored by Finapres, and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). For data analysis, CVC values for each site were normalized to their respective maxima as effected by SNP. The results showed that both Keto and l-NAME each attenuated the vasodilation induced by exogenous ACh (ACh control = 79 ± 4% maximal CVC, Keto = 55 ± 7% maximal CVC, l-NAME = 46 ± 6% maximal CVC; P < 0.05, ACh vs. Keto or l-NAME). The combination of the two agents produced an even greater attenuation of ACh-induced vasodilation (31 ± 5% maximal CVC; P < 0.05 vs. all other sites). We conclude that a portion of the vasodilation effected by exogenous ACh in skin is due to NO; however, a significant portion is also mediated by PGs.

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 New approach to measure cutaneous microvascular function: an improved test of NO-mediated vasodilation by thermal hyperemia

2014 ◽  
Vol 117 (3) ◽  
pp. 277-283 ◽  
Author(s):  
Patricia J. Choi ◽  
Vienna E. Brunt ◽  
Naoto Fujii ◽  
Christopher T. Minson
Keyword(s):  
Healthy Subjects ◽  
Rapid Heating ◽  
Local Heating ◽  
Ringer Solution ◽  
No Synthase ◽  
Microvascular Function ◽  
Vascular Conductance ◽  
New Approach ◽  
Cutaneous Vascular Conductance

Cutaneous hyperemia in response to rapid skin local heating to 42°C has been used extensively to assess microvascular function. However, the response is dependent on both nitric oxide (NO) and endothelial-derived hyperpolarizing factors (EDHFs), and increases cutaneous vascular conductance (CVC) to ∼90–95% maximum in healthy subjects, preventing the study of potential means to improve cutaneous function. We sought to identify an improved protocol for isolating NO-dependent dilation. We compared nine heating protocols (combinations of three target temperatures: 36°C, 39°C, and 42°C, and three rates of heating: 0.1°C/s, 0.1°C/10 s, 0.1°C/min) in order to select two protocols to study in more depth ( protocol 1; N = 6). Then, CVC was measured at four microdialysis sites receiving: 1) lactated Ringer solution (Control), 2) 50-mM tetraethylammonium (TEA) to inhibit EDHFs, 3) 20-mM nitro-L-arginine methyl ester (L-NAME) to inhibit NO synthase, and 4) TEA+L-NAME, in response to local heating either to 39°C at 0.1°C/s ( protocol 2; N = 10) or 42°C at 0.1°C/min ( protocol 3; N = 8). Rapid heating to 39°C increased CVC to 43.1 ± 5.2%CVCmax (Control), which was attenuated by L-NAME (11.4 ± 2.8%CVCmax; P < 0.001) such that 82.8 ± 4.2% of the plateau was attributable to NO. During gradual heating, 81.5 ± 3.3% of vasodilation was attributable to NO at 40°C, but at 42°C only 32.7 ± 7.8% of vasodilation was attributable to NO. TEA+L-NAME attenuated CVC beyond L-NAME at temperatures >40°C (43.4 ± 4.5%CVCmax at 42°C, P < 0.001 vs. L-NAME), suggesting a role of EDHFs at higher temperatures. Our findings suggest local heating to 39°C offers an improved approach for isolating NO-dependent dilation and/or assessing perturbations that may improve microvascular function.

scholarly journals Sex differences in the mechanisms mediating blunted cutaneous microvascular function in young black men and women

2018 ◽  
Vol 315 (4) ◽  
pp. H1063-H1071 ◽  
Author(s):  
Jordan C. Patik ◽  
Bryon M. Curtis ◽  
Aida Nasirian ◽  
Jennifer R. Vranish ◽  
Paul J. Fadel ◽  
...  
Keyword(s):  
Sex Differences ◽  
Black Women ◽  
Black Men ◽  
Local Heating ◽  
Black Population ◽  
Control Site ◽  
Microvascular Function ◽  
Vascular Conductance ◽  
Men And Women ◽  
Cutaneous Vascular Conductance

The black population exhibits attenuated vasodilatory function across their lifespan, yet little is known regarding the mechanisms of this impairment. Recent evidence suggests a potential role for oxidative stress. Therefore, we tested the hypothesis that NADPH oxidase (NOX) and/or xanthine oxidase (XO) contribute to blunted nitric oxide (NO)-mediated cutaneous microvascular function in young black adults. In 30 white and black subjects (8 men and 7 women in each group), local heating was performed while NOX and XO were inhibited by apocynin and allopurinol, respectively, via intradermal microdialysis. The plateau in cutaneous vascular conductance (red blood cell flux/mean arterial pressure) during 39°C local heating at each site was compared with a control site perfused with lactated Ringer solution. Subsequent inhibition of NO synthase via Nω-nitro-l-arginine methyl ester allowed for quantification of the NO contribution to vasodilation during heating. Black individuals, relative to white individuals, had a blunted cutaneous vascular conductance plateau at the control site (45 ± 9 vs. 68 ± 13%max, P < 0.001) that was increased by both apocynin (61 ± 15%max, P < 0.001) and allopurinol (58 ± 17%max, P = 0.005). Black men and black women had similar responses to heating at the control site ( P = 0.99), yet apocynin and allopurinol increased this response only in black men (both P < 0.001 vs. control). The NO contribution was also increased via apocynin and allopurinol exclusively in black men. These findings suggest that cutaneous microvascular function is reduced because of NOX and XO activity in black men but not black women, identifying a novel sex difference in the mechanisms that contribute to blunted vascular responses in the black population. NEW & NOTEWORTHY We demonstrate that cutaneous microvascular responses to local heating are consistently reduced in otherwise healthy young black men and women relative to their white counterparts. Inhibition of NADPH oxidase and xanthine oxidase via apocynin and allopurinol, respectively, augments microvascular function in black men but not black women. These data reveal clear sex differences in the mechanisms underlying the racial disparity in cutaneous microvascular function.

scholarly journals Mechanisms of vasoactive intestinal peptide-mediated vasodilation in human skin

2004 ◽  
Vol 97 (4) ◽  
pp. 1291-1298 ◽  
Author(s):  
Brad W. Wilkins ◽  
Linda H. Chung ◽  
Nathan J. Tublitz ◽  
Brett J. Wong ◽  
Christopher T. Minson
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Human Skin ◽  
Receptor Activation ◽  
No Synthase ◽  
Doppler Flowmetry ◽  
Relative Contribution ◽  
Flow Response ◽  
Receptor Inhibition ◽  
Dependent Component ◽  
Cutaneous Vascular Conductance

Vasoactive intestinal peptide (VIP) is known to induce histamine release in human skin and to include a nitric oxide (NO)-dependent dilation in several other vascular beds. However, the relative contribution of histamine and NO to VIP-mediated vasodilation in human skin is unknown. Forty-three subjects volunteered to participate in two studies designed to examine the mechanism of VIP-mediated vasodilation in human skin. Study 1 examined the contribution of NO in the skin blood flow response to eight doses of VIP ranging from 25 to 800 pmol. In addition, study 1 examined a specific role for NO in VIP-mediated dilation. Study 2 examined the relative contribution of NO and histamine to VIP-mediated dilation via H1 and H2 histamine receptors. Infusions were administered to skin sites via intradermal microdialysis. Red blood cell flux was measured by using laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC; LDF/mean arterial pressure) was calculated and normalized to maximal vasodilation. VIP-mediated vasodilation includes a NO-dependent component at doses above 100 pmol, where NO synthase inhibition significantly attenuates CVC ( P < 0.05). Inhibition of H1 receptors attenuates the rise in CVC to exogenous VIP ( P < 0.05); however, combined H1-receptor inhibition and NO synthase inhibition further reduced VIP-mediated vasodilation compared with either H1 inhibition or NO synthase inhibition alone ( P < 0.05). In contrast to H1-receptor inhibition, H2-receptor inhibition did not affect vasodilation to exogenous VIP. Thus, in human skin, VIP-mediated vasodilation includes a NO-dependent component that could not be explained by H1- and H2-receptor activation.

scholarly journals Sex- and limb-specific differences in the nitric oxide-dependent cutaneous vasodilation in response to local heating

2014 ◽  
Vol 307 (7) ◽  
pp. R914-R919 ◽  
Author(s):  
Anna E. Stanhewicz ◽  
Jody L. Greaney ◽  
W. Larry Kenney ◽  
Lacy M. Alexander
Keyword(s):  
Nitric Oxide ◽  
Local Heating ◽  
Ringer Solution ◽  
No Synthase ◽  
Site Assessment ◽  
Cutaneous Vasodilation ◽  
Dependent Component ◽  
Doppler Flux ◽  
Cutaneous Vascular Conductance ◽  
Nnos Inhibition

Local heating of the skin is commonly used to assess cutaneous microvasculature function. Controversy exists as to whether there are limb or sex differences in the nitric oxide (NO)-dependent contribution to this vasodilation, as well as the NO synthase (NOS) isoform mediating the responses. We tested the hypotheses that 1) NO-dependent vasodilation would be greater in the calf compared with the forearm; 2) total NO-dependent dilation would not be different between sexes within limb; and 3) women would exhibit greater neuronal NOS (nNOS)-dependent vasodilation in the calf. Two microdialysis fibers were placed in the skin of the ventral forearm and the calf of 19 (10 male and 9 female) young (23 ± 1 yr) adults for the local delivery of Ringer solution (control) or 5 mM Nω-propyl-l-arginine (NPLA; nNOS inhibition). Vasodilation was induced by local heating (42°C) at each site, after which 20 mM NG-nitro-l-arginine methyl ester (l-NAME) was perfused for within-site assessment of NO-dependent vasodilation. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial pressure and normalized to maximum (28 mM sodium nitroprusside, 43°C). Total NO-dependent vasodilation in the calf was lower compared with the forearm in both sexes (Ringer: 42 ± 5 vs. 62 ± 4%; P < 0.05; NPLA: 37 ± 3 vs. 59 ± 5%; P < 0.05) and total NO-dependent vasodilation was lower in the forearm for women (Ringer: 52 ± 6 vs. 71 ± 4%; P < 0.05; NPLA: 47 ± 6 vs. 68 ± 5%; P < 0.05). NPLA did not affect total or NO-dependent vasodilation across limbs in either sex ( P > 0.05). These data suggest that the NO-dependent component of local heating-induced cutaneous vasodilation is lower in the calf compared with the forearm. Contrary to our original hypothesis, there was no contribution of nNOS to NO-dependent vasodilation in either limb during local heating.

scholarly journals Cutaneous neuronal nitric oxide is specifically decreased in postural tachycardia syndrome

2007 ◽  
Vol 293 (4) ◽  
pp. H2161-H2167 ◽  
Author(s):  
Julian M. Stewart ◽  
Marvin S. Medow ◽  
Christopher T. Minson ◽  
Indu Taneja
Keyword(s):  
Nitric Oxide ◽  
Local Heating ◽  
Local Heat ◽  
Low Flow ◽  
Postural Tachycardia Syndrome ◽  
Doppler Flowmetry ◽  
Postural Tachycardia ◽  
Nos Inhibitor ◽  
Cutaneous Vascular Conductance ◽  
Nnos Inhibition

Low flow postural tachycardia syndrome (POTS), is associated with reduced nitric oxide (NO) activity assumed to be of endothelial origin. We tested the hypothesis that cutaneous microvascular neuronal NO (nNO) is impaired, rather than endothelial NO (eNO), in POTS. We performed three sets of experiments on subjects aged 22.5 ± 2 yr. We used laser-Doppler flowmetry response to sequentially increase acetylcholine (ACh) doses and the local cutaneous heating response of the calf as bioassays for NO. During local heating we showed that when the selective neuronal nNO synthase (nNOS) inhibitor Nω-nitro-l-arginine-2,4-l-diaminobutyric amide ( Nω, 10 mM) was delivered by intradermal microdialysis, cutaneous vascular conductance (CVC) decreased by an amount equivalent to the largest reduction produced by the nonselective NO synthase (NOS) inhibitor nitro-l-arginine (NLA, 10 mM). We demonstrated that the response to ACh was minimally attenuated by nNOS blockade using Nω but markedly attenuated by NLA, indicating that eNO largely comprises the receptor-mediated NO release by ACh. We further demonstrated that the ACh dose response was minimally reduced, whereas local heat-mediated NO-dependent responses were markedly reduced in POTS compared with control subjects. This is consistent with intact endothelial function and reduced NO of neuronal origin in POTS. The local heating response was highly attenuated in POTS [60 ± 6 percent maximum CVC(%CVCmax)] compared with control (90 ± 4 %CVCmax), but the plateau response decreased to the same level with nNOS inhibition (50 ± 3 %CVCmax in POTS compared with 47 ± 2 %CVCmax), indicating reduced nNO bioavailability in POTS patients. The data suggest that nNO activity but not NO of endothelial NOS origin is reduced in low-flow POTS.

scholarly journals Exogenous Antioxidants Impact on UV-Induced Changes in Membrane Phospholipids and the Effectiveness of the Endocannabinoid System in Human Skin Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1260
Author(s):  
Agnieszka Gęgotek ◽  
Anna Jastrząb ◽  
Marta Dobrzyńska ◽  
Michał Biernacki ◽  
Elżbieta Skrzydlewska
Keyword(s):  
Ascorbic Acid ◽  
Cell Viability ◽  
Human Skin ◽  
Phospholipid Fatty Acid ◽  
Antioxidant Properties ◽  
Endocannabinoid System ◽  
Membrane Phospholipids ◽  
Skin Cells ◽  
Human Skin Cells ◽  
Induced Changes

Natural antioxidants effectively counteract changes caused by UV radiation in human skin cells. However, their action is limited due to their lipo/hydrophilicity. Therefore, the aim of this study was to analyze the mutual protective action of hydrophilic ascorbic acid and partially lipophilic rutin against UVA/UVB-induced changes in membranes phospholipid and endocannabinoid system in keratinocytes and fibroblasts. Obtained results clearly showed that, despite the stronger antioxidant properties of ascorbic acid, the lipid membranes were more effectively protected against UV-induced oxidation by rutin, including changes in phospholipid fatty acid levels, prevention against reactive aldehydes formation and endocannabinoids degradation. Ascorbic acid more strongly prevented UV-induced endocannabinoid receptors expression in fibroblasts, especially CB1. However, the combined action of used antioxidants resulted in the greatest cytoprotective effect, which was evident in the inflammatory marker TNFα down-regulation and increased cell viability following cell irradiation. The applied mixture of antioxidants showed a stronger protective in relation to membrane phospholipids in keratinocytes and in the endocannabinoid system in fibroblasts. In conclusion, it can be suggested that combined antioxidant capacities of ascorbic acid and rutin protects against lipid peroxidation but also decreases the UV-induced inflammation by direct interaction with the endocannabinoid system, thus increasing skin cell viability.

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.

Sign in / Sign up

Export Citation Format

Share Document