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.

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.

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 Nitric oxide and cutaneous active vasodilation during heat stress in humans

1998 ◽  
Vol 85 (3) ◽  
pp. 824-829 ◽  
Author(s):  
D. L. Kellogg ◽  
C. G. Crandall ◽  
Y. Liu ◽  
N. Charkoudian ◽  
J. M. Johnson
Keyword(s):  
Nitric Oxide ◽  
Heat Stress ◽  
Laser Doppler Flowmetry ◽  
Sweat Rate ◽  
Ringer Solution ◽  
No Synthase ◽  
Laser Doppler ◽  
Vascular Conductance ◽  
Doppler Flowmetry ◽  
Cutaneous Vascular Conductance

Whether nitric oxide (NO) is involved in cutaneous active vasodilation during hyperthermia in humans is unclear. We tested for a role of NO in this process during heat stress (water-perfused suits) in seven healthy subjects. Two forearm sites were instrumented with intradermal microdialysis probes. One site was perfused with the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) dissolved in Ringer solution to abolish NO production. The other site was perfused with Ringer solution only. At those sites, skin blood flow (laser-Doppler flowmetry) and sweat rate were simultaneously and continuously monitored. Cutaneous vascular conductance, calculated from laser-Doppler flowmetry and mean arterial pressure, was normalized to maximal levels as achieved by perfusion with the NO donor nitroprusside through the microdialysis probes. Under normothermic conditions,l-NAME did not significantly reduce cutaneous vascular conductance. During hyperthermia, with skin temperature held at 38–38.5°C, internal temperature rose from 36.66 ± 0.10 to 37.34 ± 0.06°C ( P < 0.01). Cutaneous vascular conductance at untreated sites increased from 12 ± 2 to 44 ± 5% of maximum, but only rose from 13 ± 2 to 30 ± 5% of maximum at l-NAME-treated sites ( P < 0.05 between sites) during heat stress. l-NAME had no effect on sweat rate ( P > 0.05). Thus cutaneous active vasodilation requires functional NO synthase to achieve full expression.

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 Role of nitric oxide in the vascular effects of local warming of the skin in humans

1999 ◽  
Vol 86 (4) ◽  
pp. 1185-1190 ◽  
Author(s):  
D. L. Kellogg ◽  
Y. Liu ◽  
I. F. Kosiba ◽  
D. O’Donnell
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Control Period ◽  
No Synthase ◽  
Vascular Effects ◽  
Doppler Flowmetry ◽  
Cutaneous Vasodilation ◽  
Local Warming ◽  
Cutaneous Vascular Conductance

Local warming of skin induces vasodilation by unknown mechanisms. To test whether nitric oxide (NO) is involved, we examined effects of NO synthase (NOS) inhibition with N G-nitro-l-arginine methyl ester (l-NAME) on vasodilation induced by local warming of skin in six subjects. Two adjacent sites on the forearm were instrumented with intradermal microdialysis probes for delivery ofl-NAME and sodium nitroprusside. Skin blood flow was monitored by laser-Doppler flowmetry (LDF) at microdialysis sites. Local temperature (Tloc) of the skin at both sites was controlled with special LDF probe holders. Mean arterial pressure (MAP; Finapres) was measured and cutaneous vascular conductance calculated (CVC = LDF/MAP = mV/mmHg). Data collection began with a control period (Tloc at both sites = 34°C). One site was then warmed to 41°C while the second was maintained at 34°C. Local warming increased CVC from 1.44 ± 0.41 to 4.28 ± 0.60 mV/mmHg ( P < 0.05). Subsequent l-NAME administration reduced CVC to 2.28 ± 0.47 mV/mmHg ( P < 0.05 vs. heating), despite the continued elevation of Tloc. At a Tloc of 34°C,l-NAME reduced CVC from 1.17 ± 0.23 to 0.75 ± 0.11 mV/mmHg ( P < 0.05). Administration of sodium nitroprusside increased CVC to levels no different from those induced by local warming. Thus NOS inhibition attenuated, and sodium nitroprusside restored, the cutaneous vasodilation induced by elevation of Tloc; therefore, the mechanism of cutaneous vasodilation by local warming requires NOS generation of NO.

Oral vitamin C enhances the adrenergic vasoconstrictor response to local cooling in human skin

2012 ◽  
Vol 112 (10) ◽  
pp. 1689-1697 ◽  
Author(s):  
Fumio Yamazaki
Keyword(s):  
Human Skin ◽  
Local Administration ◽  
Adrenergic System ◽  
Local Cooling ◽  
Oral Vitamin ◽  
Vascular Conductance ◽  
Doppler Flowmetry ◽  
Vasoconstrictor Response ◽  
Forearm Skin ◽  
Cutaneous Vascular Conductance

Local administration of ascorbic acid (Asc) at a supraphysiological concentration inhibits the cutaneous vasoconstrictor response to local cooling (LC). However, whether orally ingesting Asc inhibits the LC-induced vasoconstrictor response remains unknown. The purpose of the present study was to examine the acute influence of oral Asc on the adrenergic vasoconstrictor response to LC in human skin. In experiment 1, skin blood flow (SkBF) was measured by laser-Doppler flowmetry at three sites (forearm, calf, palm). The three skin sites were locally cooled from 34 to 24°C at −1°C/min and maintained at 24°C for 20 min before (Pre) and 1.5 h after (Post) oral Asc (2-g single dose) or placebo supplementation. Cutaneous vascular conductance (CVC) was calculated as the ratio of SkBF to blood pressure and expressed relative to the baseline value before LC. Oral Asc enhanced ( P < 0.05) the reductions in CVC in the forearm (Pre, −50.3 ± 3.3%; Post, −57.8 ± 2.2%), calf (Pre, −52.6 ± 3.7%; Post, −66.1 ± 4.3%), and palm (Pre, −46.2 ± 6.2%; Post, −60.4 ± 5.6%) during LC. The placebo did not change the responses at any site. In experiment 2, to examine whether the increased vasoconstrictor response caused by oral Asc is due to the adrenergic system, the release of neurotransmitters from adrenergic nerves in forearm skin was blocked locally by iontophoresis of bretylium tosylate (BT). Oral Asc enhanced ( P < 0.05) the reductions in CVC at untreated control sites but did not change the responses at BT-treated sites during LC. In experiment 3, to further examine whether adrenergically mediated vasoconstriction is enhanced by oral Asc, 0.1 mM tyramine was administered using intradermal microdialysis in the forearm skin at 34°C in the Pre and Post periods. Oral Asc increased ( P < 0.05) the tyramine-induced reduction in CVC. These findings suggest that oral Asc acutely enhances the cutaneous vasoconstrictor responses to LC through the modification of adrenergic sympathetic mechanisms.

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 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.

Calcium regulates estrogen increase in permeability of cultured CaSki epithelium by eNOS-dependent mechanism

2000 ◽  
Vol 279 (5) ◽  
pp. C1495-C1505 ◽  
Author(s):  
George I. Gorodeski
Keyword(s):  
Nitric Oxide ◽  
Endothelial Nitric Oxide Synthase ◽  
Cytosolic Calcium ◽  
No Synthase ◽  
Calcium Dependent ◽  
Steady State Levels ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Dependent Mechanism

Estrogen increases baseline transepithelial permeability across CaSki cultures and augments the increase in permeability in response to hypertonic gradients. In estrogen-treated cells, lowering cytosolic calcium abrogated the hypertonicity-induced augmented increase in permeability and decreased baseline permeability to a greater degree than in estrogen-deprived cells. Steady-state levels of cytosolic calcium in estrogen-deprived cells were higher than in estrogen-treated cells. Increases in extracellular calcium increased cytosolic calcium more in estrogen-deprived cells than in estrogen-treated cells. However, in estrogen-treated cells, increasing cytosolic calcium was associated with greater increases in permeability in response to hypertonic gradients than in estrogen-deprived cells. Lowering cytosolic calcium blocked the estrogen-induced increase in nitric oxide (NO) release and in the in vitro conversion of l-[3H]arginine to l-[3H]citrulline. Treatment with estrogen upregulated mRNA of the NO synthase isoform endothelial nitric oxide synthase (eNOS). These results indicate that cytosolic calcium mediates the responses to estrogen and suggest that the estrogen increase in permeability and the augmented increase in permeability in response to hypertonicity involve an increase in NO synthesis by upregulation of the calcium-dependent eNOS.

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