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1 Geriatric Research,
Education, and Clinical Center, Department of Veterans
Affairs, South Texas Veterans Health Care System, Audie L. Murphy
Division, San Antonio 78284; Departments of
2 Physiology,
3 Medicine, and
4 Pharmacology, 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
NG-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.
skin blood flow; microdialysis; laser-Doppler flowmetry
IN NONGLABROUS AREAS OF SKIN in humans,
thermoregulatory reflex alterations of skin blood flow (SkBF) are
mediated by sympathetic efferent nerves of two types: active
vasoconstrictor and active vasodilator nerves (6, 10, 13, 20).
Cutaneous vasoconstrictor nerves are noradrenergic and act through
postjunctional The suggestion that ACh plays a role in active vasodilation also
suggests a mechanistic role for nitric oxide (NO) in the process.
Studies in rabbits suggest that NO produced by endothelial cells acts
in conjunction with a neurotransmitter released during hyperthermia to
increase ear blood flow (7). In humans, NO donors can increase SkBF
(26), and NO contributes to a basal dilator tone in forearm and finger
skin (4). Evidence contrary to a mechanistic role for NO in active
vasodilation has also been found. In humans, NO synthase (NOS) blockade
was found to reduce blood flow in the ventral finger, which appears to
lack active vasodilation, but not in the dorsal finger where active
vasodilation is present (12, 17). Most germane to our study, Dietz et
al. (5) found that intra-arterial infusion of the NOS inhibitor NG-monomethyl-L-arginine
(L-NMMA) blunted NO-mediated
vasodilator responses to ACh but did not significantly affect the rise
in SkBF during hyperthermia in humans.
Given this disparate evidence, we sought to test the hypothesis that NO
does play a mechanistic role in the cutaneous active vasodilator
response to heat stress in humans.
To test our hypothesis, we examined alterations of the SkBF response to
heat stress in humans during local intradermal administration of the
NOS inhibitor NG-nitro-L-arginine
methyl ester (L-NAME; Ref. 9).
The approach we chose was to combine local SkBF measurements by
laser-Doppler flowmetry (LDF) from a small volume of skin (~1
mm3) with local administration
of L-NAME by intradermal
microdialysis. Intradermal microdialysis permits local administration
of pharmacological agents directly into the interstitial space of a
small area of dermis. Monitoring LDF over a skin site instrumented with
an intradermal microdialysis probe permits monitoring of local drug
effects with high local concentrations without risking confounding
systemic effects. Because there is no question about the locus of
measurement or the locus of drug delivery, the combination of LDF with
local administration of L-NAME
provided an innovative and unambiguous approach to study the role of NO
in the control of SkBF.
Our studies were conducted at the same time that an independent group
(23) was following a different, but complementary, approach to the same
problem. In their study, intra-arterial administration of NOS
inhibitors was combined with LDF measurements of forearm SkBF and
plethysmographic measurements of total forearm blood flow (FBF) during
body heating. Our results and conclusions are consistent with those
presented in that complementary study (23).
Seven subjects (4 men and 3 women) participated in this study. Their
average age was 30 ± 4 (SE) yr, average weight 79 ± 4 kg, and
average height 176 ± 3 cm. All subjects were in good health and
were taking no medications. All subjects gave informed consent to
participate in these institutionally approved studies. There was no
caffeine intake on the day of the study. All subjects were nonsmokers.
The menstrual phase was not assessed in the female subjects.
Thermoregulatory reflexes were induced as follows. Subjects wore a
tube-lined suit used to control skin temperature
(Tsk) by perfusion with water of
different temperatures (11, 21, 24). Over the suit, subjects wore a
water-impermeable plastic garment to insulate them from the room
environment and to prevent evaporation of sweat. The suit and garment
covered the entire body except for the head, arms, and feet. The suit
was perfused with warm water to raise
Tsk to 38-39°C during
heating periods and with cold water to lower
Tsk from 34-34.5 to
31.5-32°C for cold stress.
Internal (oral; Tor) temperature
was monitored with a thermocouple placed in the sublingual sulcus.
Tsk was recorded as the weighted
electrical average from six thermocouples taped on the skin surface.
Heart rate was recorded continuously from the electrocardiogram. Mean
arterial pressure was recorded continuously from a finger (Finapres BP
Monitor, Ohmeda).
After being instrumented as outlined above, subjects had an intradermal
microdialysis probe placed at each of two sites on the ventral aspect
of one forearm. The probes were of our own manufacture and were made
from borosilicate glass tubing and a 1-cm length of capillary
microdialysis membrane (200-µm diameter, molecular cutoff 20 kDa;
Spectrum Medical Industries, Houston, TX) reinforced by a 51-µm-
diameter coated stainless steel wire placed in the lumen of the
membrane and tubing. Placement of the microdialysis probe was
accomplished at each site as follows. First, a 25-gauge needle was
inserted through the dermis by using sterile technique. Entry and exit
points were ~2.5 cm apart. The microdialysis probe was threaded
through the internal lumen of the needle. The needle was then
withdrawn, leaving the probe in place. The microdialysis membrane was
entirely within the dermis, with entry and exit through the skin via
the borosilicate tubing. Ultrasound measurements showed that probes
placed with this technique are 0.3-0.9 mm under the epidermal
surface and thus well within the dermis. Subjects then waited 140 min
or more to allow for insertion trauma to resolve before additional
instrumentation was placed. Anderson et al. (1) reported that the
injury caused by insertion of an intradermal microdialysis probe
resolves during a period of 90-135 min, thereafter allowing in
vivo studies without the confounding effects of trauma. Subjects were
then placed in the supine position and instrumented to measure LDF from
skin at the two microdialysis sites (MBF3D dual-channel flowmeter, Moor
Instruments, Devon, UK). LDF measurements are specific to skin, being
uninfluenced by blood flow in the underlying tissues (22). Sweat rate
(SR) was assessed at the two LDF-microdialysis sites by
relative-humidity monitors (HX92V, Omega Engineering; IH 3602-L
humidity sensors, HY-CAL Engineering). LDF probes were held in special
probe holders that permit simultaneous LDF and SR measurements (16).
After the LDF probes were placed, both microdialysis probes were
perfused with Ringer solution at a rate of 2 µl/min by using a
microinfusion pump.
As illustrated in Fig. 1, data collection
began with a 5- to 20-min control period followed by a 3-min
application of whole body cooling. Body cooling was used to verify that
active vasoconstrictor function was intact at the microdialysis sites
and that the trauma of probe placement had not caused either a loss of
neural or vessel reactivity. Subjects were returned to normothermia,
and one of the microdialysis probes was then perfused with a 5-mM
solution of L-NAME (Sigma
Chemical, St. Louis, MO) dissolved in Ringer solution. This dose was
chosen based on studies of the role of NOS in the vasodilation induced
by local warming (15). In those studies, we examined the effect of
1.25-, 2.5-, 5-, 10-, and 20-mM concentrations of
L-NAME delivered by intradermal
microdialysis and found no significant difference in the
vasoconstriction induced by the higher three doses. Thus the 5-mM
concentration was chosen for the present study.
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
1- and 2- receptors (13,
17). This system is activated during periods of cold stress to reduce
SkBF and conserve body heat. Studies of thermoregulatory reflexes in
resting subjects have shown that during heat stress there is an initial
abolition of any extant vasoconstrictor tone. As internal temperature
increases further, the active vasodilator system is activated along
with sweat production. The active vasodilator system is responsible for
80-95% of the elevation in SkBF accompanying heat stress (13).
Cutaneous active vasodilation is effected by a cholinergic
cotransmitter system, as the process is completely abolished by
intradermal botulinum toxin (16) but not by atropine. Muscarinic
blockade with atropine slightly reduces or delays vasodilator responses
to hyperthermia, although it completely abolishes the response to
exogenous acetylcholine (ACh) (16, 20). The failure to block
vasodilation has generally been taken as evidence against a role for
ACh as the neurotransmitter substance involved; however, the partial
inhibitory effect of atropine on the process suggests a role for ACh.
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
View larger version (23K):
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Fig. 1.
Illustration of protocol and results of the study in 1 subject. Periods
of cold stress (CS; CS1 and CS2), whole body heating, and sodium
nitroprusside infusion (SNP) are noted at
bottom. Beginning of perfusion of 1 microdialysis probe with 5 mM
NG-nitro-L-arginine methyl ester
(L-NAME) in Ringer
solution is also shown. Note that increase in cutaneous vascular
conductance (CVC) during whole body heating was attenuated at the site
receiving L-NAME, but
sweat rate response was unaltered. T oral, oral temperature.
After 40 min of perfusion with L-NAME, the 3-min period of cold stress was repeated to test for any effects of the drug on vasoconstrictor function. After a few minutes of recovery, Tsk was raised to 38-39°C and was maintained at that level for 35-50 min to induce heat stress and thus activate the vasodilator system. After hyperthermia, subjects were cooled to normothermia, and both microdialysis probes were perfused with 28 mM of nitroprusside (Sigma Chemical) in Ringer solution for 20-40 min to effect maximal vasodilation (15). Nitroprusside infusion was chosen for maximal vasodilation, in lieu of local skin warming (14, 24), since NOS activity is required for cutaneous vasodilation as induced by local warming (15). Thus the administration of L-NAME in the present study precluded the use of local warming of the skin to achieve maximal levels of blood flow. The dose of nitroprusside chosen dilates cutaneous vessels to maximal levels no different from those achievable by raising the local temperature of the skin to 42°C (15).
Data are means ± SE. For data analysis, cutaneous vascular conductance (CVC) was indexed as LDF (in mV) divided by MAP (in mmHg) and normalized to the maximal levels, as achieved with nitroprusside to allow site-to-site and subject-to subject comparisons of responses in CVC (14, 15). The vasomotor responses during each of the separate periods of cold stress were analyzed by comparing the pre-cold stress levels of CVC with the levels achieved during the last minute of cold stress. The vasomotor responses to heat stress were analyzed by comparing pre-heat stress levels of CVC with the levels achieved during the last minute of heat stress. The degree of vasodilation was compared between untreated and L-NAME-treated sites on the basis of the percentage of maximal CVC for those sites. Sudomotor responses were analyzed by comparing pre-heat stress levels of SR with the levels achieved during the last minute of heat stress. Internal temperature thresholds (the level of Tor at which CVC began to rise during whole body heating) were chosen from plots of CVC vs. Tor by an investigator blinded to the conditions, subjects, and drug treatments involved. Tor responses were analyzed by paired t-test that compared internal temperature thresholds at L-NAME-treated and untreated sites. CVC and SR responses were analyzed by repeated-measures ANOVA followed by planned contrasts.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Figure 1 illustrates the results from one subject. Before the perfusion of one microdialysis site with L-NAME, CVC for the entire subject group did not differ significantly between sites, nor did the responses differ during whole body cooling (P > 0.05). During the initial control period, CVC levels at the two microdialysis sites averaged 15 ± 4 and 20 ± 6% of the maximal level (%max; P > 0.05). During the initial cold stress, CVC fell by 4 ± 0.5 (P < 0.05 vs. control) and 7 ± 2.0% (P < 0.05 vs. control) of the maximal CVCs at the different microdialysis sites. These responses were not statistically different (P > 0.05). Up to this point in the protocol, both sites were perfused with Ringer solution only. (Data for the probe to be perfused with the L-NAME solution are given second.)
Under normothermic conditions, perfusion with L-NAME for 40 min did not significantly reduce CVC at the treated site (20 ± 6%max pre-L-NAME to 13 ± 2%max post-L-NAME, P > 0.05). During the repetition of cold stress, at the site treated with L-NAME, CVC fell by 4 ± 0.6%max (P < 0.05 vs. pre-cold stress). CVC fell by 4 ± 1.0%max (P < 0.05 vs. pre-cold stress) of the maximal level at the untreated sites. These responses did not significantly differ (P > 0.50) and are summarized in Fig. 2.
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Before initiation of whole body heating, Tor averaged 36.66 ± 0.10°C. During whole body heating, vasodilation began at the untreated microdialysis sites when Tor reached a threshold value of 37.00 ± 0.10°C. At the L-NAME-treated sites, vasodilation began when Tor reached 37.08 ± 0.06°C (P > 0.15 between sites). Tor reached 37.34 ± 0.05°C at the peak of heat stress (P < 0.01 preheating vs. peak heat stress). During heat stress, CVC rose at both untreated and L-NAME treated sites; however, the rise was attenuated by L-NAME treatment. At the peak of heat stress, CVC at the untreated site reached 44 ± 2%max levels (P < 0.05 vs. preheating), whereas at the L-NAME-treated sites CVC reached only 30 ± 5%max levels (P < 0.05 vs. preheating). Thus L-NAME treatment significantly attenuated the thermoregulatory increase in CVC during whole body heating (P < 0.05 between sites). These results are summarized in Fig. 2. SR responses did not differ between untreated and L-NAME-treated sites during heat stress (P > 0.25).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The results of this study show that full expression of cutaneous active vasodilation in humans requires NOS activity. This conclusion derives from the observation that blockade of NOS by L-NAME significantly attenuated the reflex increase in CVC in response to whole body heat stress. The attenuation was not likely due to any antimuscarinic effects of L-NAME (3), as the SR response to heat stress was not altered by the agent.
The results of the initial cold stress, during the perfusion with Ringer solution only, demonstrated that the ability of the cutaneous vessels to respond to increased noradrenergic vasoconstrictor tone persisted after microdialysis probe placement. Thus trauma associated with placement of the probes did not render the vessels incapable of responding to neural inputs. The ability of the vessels to vasoconstrict during cold stress was also preserved after treatment with L-NAME. This demonstrates that NOS inhibition did not alter responses to activation of noradrenergic vasoconstrictor nerves. This finding is consistent with those of Coffman (4), who found that NOS inhibition with L-NMMA had no effect on the reduction in finger blood flow or FBF accompanying whole body cooling. This evidence suggests little or no role for NO in the control of SkBF during cooling.
Over the course of L-NAME infusion during normothermia, there was a trend for a reduction in CVC, although this did not reach statistical significance. Such a reduction was reported by Coffman (4), who recorded reductions in LDF during intra-arterial infusion of L-NMMA during normothermia; however, no reduction was found under cool conditions. In support of Coffman's work, Dietz et al. (5) reported that FBF was reduced during infusion of L-NMMA into the brachial artery, although the distribution of this reduction between skin and muscle is not known. In contrast, Noon et al. (18) reported that, despite reduction in FBF during intra-arterial infusion of L-NMMA at doses of 1, 2, and 4 µM/min, there was no reduction in LDF from skin on the dorsum of the finger. The different findings might be attributable to differing thermal conditions, reductions in SkBF by NOS inhibition being evident at the higher levels of blood flow due to inhibition of flow-induced NO release in normothermia.
Our results contrast with those of Dietz et al. (5), in which unilateral infusion of L-NMMA into the brachial artery did not attenuate the increase in forearm SkBF during hyperthermia. As acknowledged by the authors, they were only able to consistently verify L-NMMA blockade of the vasodilator response to exogenous ACh during normothermia, allowing the possibility that blockade of NOS was incomplete during heat stress. This possibility is strengthened by the more recent results from that laboratory, presented in a companion study (23). It is also possible that our doses of L-NAME did not block NOS activity completely. Thus we are not able to say whether the mechanism is entirely NO-dependent or whether NO-independent pathways are involved in cutaneous active vasodilation.
Inhibition of the elevation of SkBF with L-NMMA during hyperthermia by Shastry et al. (23) confirms that the choice of NOS inhibitor does not explain the differences in results between our study and that of Dietz et al. (5). However, our use of intradermal microdialysis to continuously deliver relatively large doses of drug ensured significant NOS inhibition throughout the study. However, given the similar results from the different approaches of microdialysis with LDF, and intra-arterial infusion with venous-occlusion plethysmography (25), we are confident that full expression of active vasodilation requires the presence of functional NOS.
The cutaneous active vasodilator system is known to be a cholinergic cotransmitter system, as active vasodilation is abolished by cholinergic nerve blockade with botulinum toxin but is only attenuated by atropine (16). These observations suggest a number of possible roles for NO in active vasodilation, although the present data do not distinguish among those possibilities. For example, a relationship between active vasodilation and sudomotor activity has been postulated (2, 8). It is interesting to speculate that released ACh causes hyperemia around activated sweat glands. Because ACh elicits vasodilation through an NO-dependent mechanism, it is possible that NOS blockade attenuated full expression of active vasodilation by reducing ACh- mediated glandular hyperemia. The cotransmitter could cause vasodilation in areas of skin remote from sweat glands and need not be NO dependent.
An alternative to the foregoing hypothesis derives from work by Farrell and Bishop (7). This hypothesis and its supporting evidence are derived from studies in the rabbit ear and suggest that NO produced by endothelial cells acts in conjunction with a neurotransmitter released during hyperthermia to effect increases in ear blood flow. According to this scheme, NO generated by endothelial cells mediates increases in cGMP, which is necessary for thermoregulatory reflex active vasodilation. However, this tonically produced NO acts in a permissive fashion with a neurogenic reflex activation of cAMP synthesis. Given the above results from Dietz et al. (5), Farrell and Bishop (7) speculated that humans may possess mechanisms other than NO that contribute to the level of cGMP. In that case, even with complete NOS blockade, the level of cGMP would be sufficient to permit vasodilation in the hyperthermic human. Our observation and that of Shastry et al. (23) of attenuation, but not abolition, of active vasodilation during heat stress is consistent with this proposal. Furthermore, it is possible that the NO involved in the vasodilation might be induced by shear stress and not by heat stress (4).
A third possibility is that nitroxidergic nerves partially effect active vasodilation in humans. Such neurally mediated vasodilation has been reported in other regions (19, 25). Such nerves are generally considered to be nonadrenergic, noncholinergic in nature (19, 25). Although the results of the present study do not exclude the possibility that nitroxidergic nerves are involved in cutaneous active vasodilation, the observation that botulinum toxin abolishes vasodilation argues against such a role (16).
In summary, we found that blockade of NOS with L-NAME attenuates, but does not abolish, thermoregulatory reflex-mediated cutaneous active vasodilation in humans. Thus NO generation is involved in the mechanism of cutaneous active vasodilation in humans.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. David Boggett of Moor Instruments, Ltd., for his generous support of our studies. The authors are grateful to the volunteers for their participation in these studies. We also thank Dermot O'Donnell and Robyn Etzel for their technical assistance.
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FOOTNOTES |
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This research was supported by the American Heart Association, Texas Affiliate, Grants 94G374 and 96R374 to D. L. Kellogg, Jr.; and by Grant 96G380 and National Heart, Lung, and Blood Institute Grant HL-36080 to J. M. Johnson.
Address for reprint requests: D. L. Kellogg, Jr., Divisions of Geriatrics and Gerontology and of Clinical Pharmacology, Dept. of Medicine, Univ. of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284 (E-mail: kelloggd{at}uthscsa.edu).
Received 27 October 1997; accepted in final form 8 May 1998.
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References
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L. A. Holowatz and W. L. Kenney Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation in middle-aged humans J Appl Physiol, February 1, 2009; 106(2): 500 - 505. [Abstract] [Full Text] [PDF]
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L. A. Sokolnicki, N. A. Strom, S. K. Roberts, S. A. Kingsley-Berg, A. Basu, and N. Charkoudian Skin blood flow and nitric oxide during body heating in type 2 diabetes mellitus J Appl Physiol, February 1, 2009; 106(2): 566 - 570. [Abstract] [Full Text] [PDF]
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M. Shibasaki, D. A. Low, S. L. Davis, and C. G. Crandall Nitric oxide inhibits cutaneous vasoconstriction to exogenous norepinephrine J Appl Physiol, November 1, 2008; 105(5): 1504 - 1508. [Abstract] [Full Text] [PDF]
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 M. A. Black, D. J. Green, and N. T. Cable Exercise prevents age-related decline in nitric-oxide-mediated vasodilator function in cutaneous microvessels J. Physiol., July 15, 2008; 586(14): 3511 - 3524. [Abstract] [Full Text] [PDF]
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 D. L. Kellogg Jr., J. L. Zhao, and Y. Wu Endothelial nitric oxide synthase control mechanisms in the cutaneous vasculature of humans in vivo Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H123 - H129. [Abstract] [Full Text] [PDF]
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D. L. Kellogg Jr, J. L. Zhao, and Y. Wu Neuronal nitric oxide synthase control mechanisms in the cutaneous vasculature of humans in vivo J. Physiol., February 1, 2008; 586(3): 847 - 857. [Abstract] [Full Text] [PDF]
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F. Yamazaki, K. Takahara, R. Sone, and J. M. Johnson Influence of hyperoxia on skin vasomotor control in normothermic and heat-stressed humans J Appl Physiol, December 1, 2007; 103(6): 2026 - 2033. [Abstract] [Full Text] [PDF]
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M. Shibasaki, S. Durand, S. L. Davis, J. Cui, D. A. Low, D. M. Keller, and C. G. Crandall Endogenous nitric oxide attenuates neutrally mediated cutaneous vasoconstriction J. Physiol., December 1, 2007; 585(2): 627 - 634. [Abstract] [Full Text] [PDF]
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S. Lorenzo and C. T. Minson Human cutaneous reactive hyperaemia: role of BKCa channels and sensory nerves J. Physiol., November 15, 2007; 585(1): 295 - 303. [Abstract] [Full Text] [PDF]
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J. M. Stewart, M. S. Medow, C. T. Minson, and I. Taneja Cutaneous neuronal nitric oxide is specifically decreased in postural tachycardia syndrome Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2161 - H2167. [Abstract] [Full Text] [PDF]
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D. L. Kellogg Jr., G. J. Hodges, C. R. Orozco, T. M. Phillips, J. L. Zhao, and J. M. Johnson Cholinergic mechanisms of cutaneous active vasodilation during heat stress in cystic fibrosis J Appl Physiol, September 1, 2007; 103(3): 963 - 968. [Abstract] [Full Text] [PDF]
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L. A. Holowatz and W. L. Kenney Local ascorbate administration augments NO- and non-NO-dependent reflex cutaneous vasodilation in hypertensive humans Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1090 - H1096. [Abstract] [Full Text] [PDF]
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B. W. Wilkins, E. A. Martin, S. K. Roberts, and M. J. Joyner Preserved reflex cutaneous vasodilation in cystic fibrosis does not include an enhanced nitric oxide-dependent mechanism J Appl Physiol, June 1, 2007; 102(6): 2301 - 2306. [Abstract] [Full Text] [PDF]
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L. A. Holowatz and W. L. Kenney Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans J. Physiol., June 1, 2007; 581(2): 863 - 872. [Abstract] [Full Text] [PDF]
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J. M. Johnson How does skin blood flow get so high? J. Physiol., December 15, 2006; 577(3): 768 - 768. [Full Text] [PDF]
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B. J. Wong and C. T. Minson Neurokinin-1 receptor desensitization attenuates cutaneous active vasodilatation in humans J. Physiol., December 15, 2006; 577(3): 1043 - 1051. [Abstract] [Full Text] [PDF]
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J. L. McCord and J. R. Halliwill H1 and H2 receptors mediate postexercise hyperemia in sedentary and endurance exercise-trained men and women J Appl Physiol, December 1, 2006; 101(6): 1693 - 1701. [Abstract] [Full Text] [PDF]
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L. A. Holowatz, C. S. Thompson, and W. L. Kenney Acute ascorbate supplementation alone or combined with arginase inhibition augments reflex cutaneous vasodilation in aged human skin Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2965 - H2970. [Abstract] [Full Text] [PDF]
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 G. R. McCord, J.-L. Cracowski, and C. T. Minson Prostanoids contribute to cutaneous active vasodilation in humans Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R596 - R602. [Abstract] [Full Text] [PDF]
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L. A. Holowatz, C. S. Thompson, and W. L. Kenney L-Arginine supplementation or arginase inhibition augments reflex cutaneous vasodilatation in aged human skin J. Physiol., July 15, 2006; 574(2): 573 - 581. [Abstract] [Full Text] [PDF]
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D. L. Kellogg Jr In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges J Appl Physiol, May 1, 2006; 100(5): 1709 - 1718. [Abstract] [Full Text] [PDF]
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K. Lee and G. W. Mack Role of nitric oxide in methacholine-induced sweating and vasodilation in human skin J Appl Physiol, April 1, 2006; 100(4): 1355 - 1360. [Abstract] [Full Text] [PDF]
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 D. J. Green, A. J. Maiorana, J. H. J. Siong, V. Burke, M. Erickson, C. T. Minson, W. Bilsborough, and G. O'Driscoll Impaired skin blood flow response to environmental heating in chronic heart failure Eur. Heart J., February 1, 2006; 27(3): 338 - 343. [Abstract] [Full Text] [PDF]
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F. Yamazaki, R. Sone, K. Zhao, G. E. Alvarez, W. A. Kosiba, and J. M. Johnson Rate dependency and role of nitric oxide in the vascular response to direct cooling in human skin J Appl Physiol, January 1, 2006; 100(1): 42 - 50. [Abstract] [Full Text] [PDF]
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J. L. McCord, J. M. Beasley, and J. R. Halliwill H2-receptor-mediated vasodilation contributes to postexercise hypotension J Appl Physiol, January 1, 2006; 100(1): 67 - 75. [Abstract] [Full Text] [PDF]
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B. W. Wilkins, B. J. Wong, N. J. Tublitz, G. R. McCord, and C. T. Minson Vasoactive intestinal peptide fragment VIP10-28 and active vasodilation in human skin J Appl Physiol, December 1, 2005; 99(6): 2294 - 2301. [Abstract] [Full Text] [PDF]
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 M. S. Medow, C. T. Minson, and J. M. Stewart Decreased Microvascular Nitric Oxide-Dependent Vasodilation in Postural Tachycardia Syndrome Circulation, October 25, 2005; 112(17): 2611 - 2618. [Abstract] [Full Text] [PDF]
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J. Cui, A. Arbab-Zadeh, A. Prasad, S. Durand, B. D. Levine, and C. G. Crandall Effects of Heat Stress on Thermoregulatory Responses in Congestive Heart Failure Patients Circulation, October 11, 2005; 112(15): 2286 - 2292. [Abstract] [Full Text] [PDF]
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 V L Clifton, R Crompton, M A Read, P G Gibson, R Smith, and I M R Wright Microvascular effects of corticotropin-releasing hormone in human skin vary in relation to estrogen concentration during the menstrual cycle J. Endocrinol., July 1, 2005; 186(1): 69 - 76. [Abstract] [Full Text] [PDF]
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G. R. McCord and C. T. Minson Cutaneous vascular responses to isometric handgrip exercise during local heating and hyperthermia J Appl Physiol, June 1, 2005; 98(6): 2011 - 2018. [Abstract] [Full Text] [PDF]
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T. E. Wilson, J. Cui, and C. G. Crandall Mean body temperature does not modulate eccrine sweat rate during upright tilt J Appl Physiol, April 1, 2005; 98(4): 1207 - 1212. [Abstract] [Full Text] [PDF]
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M. Tartas, P. Bouye, A. Koitka, S. Durand, Y. Gallois, J. L. Saumet, and P. Abraham Early vasodilator response to anodal current application in human is not impaired by cyclooxygenase-2 blockade Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1668 - H1673. [Abstract] [Full Text] [PDF]
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L. A Holowatz, C. S Thompson, C. T Minson, and W. L. Kenney Mechanisms of acetylcholine-mediated vasodilatation in young and aged human skin J. Physiol., March 15, 2005; 563(3): 965 - 973. [Abstract] [Full Text] [PDF]
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J. M Lockwood, B. W Wilkins, and J. R Halliwill H1 receptor-mediated vasodilatation contributes to postexercise hypotension J. Physiol., March 1, 2005; 563(2): 633 - 642. [Abstract] [Full Text] [PDF]
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D. L. Kellogg Jr., J. L. Zhao, U. Coey, and J. V. Green Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin J Appl Physiol, February 1, 2005; 98(2): 629 - 632. [Abstract] [Full Text] [PDF]
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S. Durand, S. L. Davis, J. Cui, and C. G. Crandall Exogenous nitric oxide inhibits sympathetically mediated vasoconstriction in human skin J. Physiol., January 15, 2005; 562(2): 629 - 634. [Abstract] [Full Text] [PDF]
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J. Stewart, A. Kohen, D. Brouder, F. Rahim, S. Adler, R. Garrick, and M. S. Goligorsky Noninvasive interrogation of microvasculature for signs of endothelial dysfunction in patients with chronic renal failure Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2687 - H2696. [Abstract] [Full Text] [PDF]
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B. J Wong, B. W Wilkins, and C. T Minson H1 but not H2 histamine receptor activation contributes to the rise in skin blood flow during whole body heating in humans J. Physiol., November 1, 2004; 560(3): 941 - 948. [Abstract] [Full Text] [PDF]
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B. W. Wilkins, L. H. Chung, N. J. Tublitz, B. J. Wong, and C. T. Minson Mechanisms of vasoactive intestinal peptide-mediated vasodilation in human skin J Appl Physiol, October 1, 2004; 97(4): 1291 - 1298. [Abstract] [Full Text] [PDF]
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J. L. Zhao, P. E. Pergola, L. J. Roman, and D. L. Kellogg Jr. Bioactive nitric oxide concentration does not increase during reactive hyperemia in human skin J Appl Physiol, February 1, 2004; 96(2): 628 - 632. [Abstract] [Full Text] [PDF]
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L. A. T Bennett, J. M Johnson, D. P Stephens, A. R Saad, and D. L Kellogg Jr Evidence for a Role for Vasoactive Intestinal Peptide in Active Vasodilatation in the Cutaneous Vasculature of Humans J. Physiol., October 1, 2003; 552(1): 223 - 232. [Abstract] [Full Text] [PDF]
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G. P. Kenny, J. Periard, W. S. Journeay, R. J. Sigal, and F. D. Reardon Cutaneous active vasodilation in humans during passive heating postexercise J Appl Physiol, September 1, 2003; 95(3): 1025 - 1031. [Abstract] [Full Text] [PDF]
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B. J. Wong, B. W. Wilkins, L. A. Holowatz, and C. T. Minson Nitric oxide synthase inhibition does not alter the reactive hyperemic response in the cutaneous circulation J Appl Physiol, August 1, 2003; 95(2): 504 - 510. [Abstract] [Full Text] [PDF]
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S. Durand, B. Fromy, M. Tartas, A. Jardel, J. L. Saumet, and P. Abraham Prolonged aspirin inhibition of anodal vasodilation is not due to the trafficking delay of neural mediators Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R155 - R161. [Abstract] [Full Text] [PDF]
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D. L. Kellogg Jr., J. L. Zhao, C. Friel, and L. J. Roman Nitric oxide concentration increases in the cutaneous interstitial space during heat stress in humans J Appl Physiol, May 1, 2003; 94(5): 1971 - 1977. [Abstract] [Full Text] [PDF]
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 N. Charkoudian Skin Blood Flow in Adult Human Thermoregulation: How It Works, When It Does Not, and Why Mayo Clin. Proc., May 1, 2003; 78(5): 603 - 612. [Abstract] [PDF]
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L. A. Holowatz, B. L. Houghton, B. J. Wong, B. W. Wilkins, A. W. Harding, W. L. Kenney, and C. T. Minson Nitric oxide and attenuated reflex cutaneous vasodilation in aged skin Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1662 - H1667. [Abstract] [Full Text] [PDF]
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I. C Roddie Sympathetic vasodilatation in human skin J. Physiol., April 15, 2003; 548(2): 336 - 337. [Full Text] [PDF]
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M. Shibasaki, T. E. Wilson, J. Cui, and C. G. Crandall Acetylcholine released from cholinergic nerves contributes to cutaneous vasodilation during heat stress J Appl Physiol, December 1, 2002; 93(6): 1947 - 1951. [Abstract] [Full Text] [PDF]
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 P. O. Scumpia, P. J. Sarcia, V. G. DeMarco, B. R. Stevens, and J. W. Skimming Hypothermia attenuates iNOS, CAT-1, CAT-2, and nitric oxide expression in lungs of endotoxemic rats Am J Physiol Lung Cell Mol Physiol, December 1, 2002; 283(6): L1231 - L1238. [Abstract] [Full Text] [PDF]
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C. T. Minson, L. A. Holowatz, B. J. Wong, W. L. Kenney, and B. W. Wilkins Decreased nitric oxide- and axon reflex-mediated cutaneous vasodilation with age during local heating J Appl Physiol, November 1, 2002; 93(5): 1644 - 1649. [Abstract] [Full Text] [PDF]
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D. L. Kellogg Jr., Y. Liu, K. McAllister, C. Friel, and P. E. Pergola Bradykinin does not mediate cutaneous active vasodilation during heat stress in humans J Appl Physiol, October 1, 2002; 93(4): 1215 - 1221. [Abstract] [Full Text] [PDF]
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 G. F. Clough, P. Boutsiouki, M. K. Church, and C. C. Michel Effects of Blood Flow on the in Vivo Recovery of a Small Diffusible Molecule by Microdialysis in Human Skin J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 681 - 686. [Abstract] [Full Text] [PDF]
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C G Crandall, M Shibasaki, and T C Yen Evidence that the human cutaneous venoarteriolar response is not mediated by adrenergic mechanisms J. Physiol., January 15, 2002; 538(2): 599 - 605. [Abstract] [Full Text] [PDF]
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M. J. Joyner, N. M. Dietz, and J. T. Shepherd From Belfast to Mayo and beyond: the use and future of plethysmography to study blood flow in human limbs J Appl Physiol, December 1, 2001; 91(6): 2431 - 2441. [Abstract] [Full Text] [PDF]
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C. J Weisbrod, C. T Minson, M. J Joyner, and J. R Halliwill Effects of regional phentolamine on hypoxic vasodilatation in healthy humans J. Physiol., December 1, 2001; 537(2): 613 - 621. [Abstract] [Full Text] [PDF]
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D. L. Kellogg Jr., Y. Liu, and P. E. Pergola Genome and Hormones: Gender Differences in Physiology: Selected Contribution: Gender differences in the endothelin-B receptor contribution to basal cutaneous vascular tone in humans J Appl Physiol, November 1, 2001; 91(5): 2407 - 2411. [Abstract] [Full Text] [PDF]
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D. P. Stephens, N. Charkoudian, J. M. Benevento, J. M. Johnson, and J. L. Saumet The influence of topical capsaicin on the local thermal control of skin blood flow in humans Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R894 - R901. [Abstract] [Full Text] [PDF]
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G. W. Mack, D. Cordero, and J. Peters Baroreceptor modulation of active cutaneous vasodilation during dynamic exercise in humans J Appl Physiol, April 1, 2001; 90(4): 1464 - 1473. [Abstract] [Full Text] [PDF]
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M. Shibasaki and C. G. Crandall Effect of local acetylcholinesterase inhibition on sweat rate in humans J Appl Physiol, March 1, 2001; 90(3): 757 - 762. [Abstract] [Full Text] [PDF]
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K. L. Ryan, M. R. Tehrany, and J. R. Jauchem Nitric oxide does not contribute to the hypotension of heatstroke J Appl Physiol, March 1, 2001; 90(3): 961 - 970. [Abstract] [Full Text] [PDF]
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C. G. Crandall and D. A. MacLean Cutaneous interstitial nitric oxide concentration does not increase during heat stress in humans J Appl Physiol, March 1, 2001; 90(3): 1020 - 1024. [Abstract] [Full Text] [PDF]
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S. Shastry, C. T. Minson, S. A. Wilson, N. M. Dietz, and M. J. Joyner Effects of atropine and L-NAME on cutaneous blood flow during body heating in humans J Appl Physiol, February 1, 2000; 88(2): 467 - 472. [Abstract] [Full Text] [PDF]
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D. L. Kellogg Jr., Y. Liu, I. F. Kosiba, and D. O'Donnell Role of nitric oxide in the vascular effects of local warming of the skin in humans J Appl Physiol, April 1, 1999; 86(4): 1185 - 1190. [Abstract] [Full Text] [PDF]
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S. Shastry, N. M. Dietz, J. R. Halliwill, A. S. Reed, and M. J. Joyner Effects of nitric oxide synthase inhibition on cutaneous vasodilation during body heating in humans J Appl Physiol, September 1, 1998; 85(3): 830 - 834. [Abstract] [Full Text] [PDF]
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C. G. Crandall, M. Shibasaki, and T.C. Yen Evidence that the human cutaneous venoarteriolar response is not mediated by adrenergic mechanisms J. Physiol., December 14, 2001; (2001) 200101306. [Abstract] [PDF]
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