© 1995 American Heart Association, Inc.
Articles |
Cutaneous Active Vasodilation in Humans Is Mediated by Cholinergic Nerve Cotransmission
From the Departments of Medicine, Physiology, Ophthalmology, and Pharmacology, University of Texas Health Science Center at San Antonio (Tex).
Correspondence to Dean L. Kellogg, Jr, MD, PhD, Division of Geriatrics and Gerontology, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78284.
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Abstract |
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Abstract During heat stress, increases in blood flow in nonglabrous skin in humans are mediated through active vasodilation by an unknown neurotransmitter mechanism. To investigate this mechanism, a three-part study was performed to determine the following: (1) Is muscarinic receptor activation necessary for active cutaneous vasodilation? We iontophoretically applied atropine to a small area of forearm skin. At that site and an untreated control site, we measured the vasomotor (laser-Doppler blood flow [LDF]) and sudomotor (relative humidity) responses to whole-body heat stress. Blood pressure was monitored. Cutaneous vascular conductance (CVC) was calculated (LDF÷mean arterial pressure). Sweating was blocked at treated sites only. CVC rose at both sites (P<.05 at each site); thus, cutaneous active vasodilation is not effected through muscarinic receptors. (2) Are nonmuscarinic cholinergic receptors present on cutaneous arterioles? Acetylcholine (ACh) was iontophoretically applied to forearm skin at sites pretreated by atropine iontophoresis and at untreated sites. ACh increased CVC at untreated sites (P<.05) but not at atropinized sites. Thus, the only functional cholinergic receptors on cutaneous vessels are muscarinic. (3) Does cutaneous active vasodilation involve cholinergic nerve cotransmission? Botulinum toxin was injected intradermally in the forearm to block release of ACh and any coreleased neurotransmitters. Heat stress was performed as in part 1 of the study. At treated sites, CVC and relative humidity remained at baseline levels during heat stress (P>.05). Active vasodilator and sudomotor responses to heat stress were abolished by botulinum toxin. We conclude that cholinergic nerve activation mediates cutaneous active vasodilation through release of an unknown cotransmitter, not through ACh.
Key Words: skin blood flow • cotransmitters • active vasodilation • muscarinic receptors • laser-Doppler flowmetry
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Introduction |
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Reflex control of blood flow to nonglabrous skin in humans is accomplished by two branches of the sympathetic nervous system: a noradrenergic active vasoconstrictor system and an active vasodilator system of uncertain neurotransmitter.1 2 3 4 5 6 7 During cold stress, vasoconstrictor nerve activity is increased, and any vasodilator activity is abolished, reducing CVC, decreasing SkBF, and conserving body heat.5 6 7 At the onset of heat stress, as internal temperature rises, an initial abolition of noradrenergic vasoconstrictor nerve activity occurs. With further increases in internal temperature, the active vasodilator system is activated. These changes in nerve activity relax cutaneous resistance vessels, thus increasing CVC and SkBF to aid in the dissipation of body heat. The activation of the vasodilator system is responsible for 80% to 95% of the elevation in SkBF accompanying heat stress.5 6 7 Considering that whole-body SkBF can achieve a level approaching 8 L/min, or 60% of cardiac output during heat stress,5 6 7 this vasodilator system is a critical component of thermoregulatory responses and can have an important role in systemic hemodynamics.
Active vasoconstrictor nerves are known to be adrenergic, secreting
norepinephrine, which acts on postsynaptic
1- and perhaps
2-receptors.5 6 7 8 Cotransmission may also be
involved in active vasoconstriction.9 10 In contrast, the
neurotransmitter and neural mechanism for active vasodilation are
unclear.11 The observation that SkBF tends to parallel
sudomotor activity during heat stress led to the suggestion that sweat
gland activation plays a role in cutaneous active vasodilation. Drawing
on earlier work done with salivary glands,12 Fox and
Hilton2 proposed that cholinergic activation of sweat
glands elicited a glandular production of kininogenase that
ultimately resulted in bradykinin production via an enzymatic
cascade. Bradykinin was proposed as the effector of active cutaneous
vasodilation, although atropine completely blocked sweat
production and only slightly delayed active vasodilation during
heat stress.2 They also detected a bradykinin-forming
enzyme in human sweat.2 Subsequent work by Frewin et
al13 failed to confirm this proposal. Although there is
agreement that systemic administration of atropine can abolish
sweating, active vasodilation is reported to be delayed in
onset,2 14 unchanged in onset,15 reduced in
magnitude,13 completely inhibited,16 or
enhanced15 by atropine. These inconsistencies suggest that
cutaneous active vasodilation may not be mediated by activation of
muscarinic receptors and does not require the activation of sweat
glands. Alternatively, another cholinergic receptor type on the skin
vessels could mediate active vasodilation. These conflicting results
even suggest that cutaneous active vasodilation may be effected by
noncholinergic nerves. However, the postulate that
cholinergic-muscarinic sudomotor activity effects active cutaneous
vasodilation persists.2 5 6 7 16
The foregoing proposals are based on principles of classic pharmacology. An alternative hypothesis proposed by Hökfelt et al17 derives from studies of cotransmitter systems in the cat paw. According to this hypothesis, a single set of cholinergic nerves could control both active dilation of cutaneous arterioles and sweating through corelease of ACh and VIP. ACh would stimulate sweating, whereas coreleased VIP would cause active vasodilation. This colocalization and corelease mechanism could explain why systemic atropine blocks sweating but has inconsistent effects on active vasodilation. In testing this hypothesis, Savage et al18 found active vasodilation to be normal in patients with cystic fibrosis, a group having very low VIP content in cutaneous postganglionic neurons. Although VIP as a cotransmitter is largely ruled out by this finding, the possibility of cholinergic cotransmission as the mechanism for cutaneous active vasodilation is not excluded.
To elucidate the mechanism of cutaneous active vasodilation in humans, we performed a study with three protocols to examine the potential involvement of muscarinic cholinergic systems, nonmuscarinic cholinergic systems, and cholinergic cotransmitter systems. Thus, the following protocols were designed to test three related hypotheses: (1) Is muscarinic control part of cutaneous active vasodilation? (2) If not, can nonmuscarinic cholinergic receptors mediate cutaneous active vasodilation? (3) If not, is cutaneous active vasodilation a function of release of a cotransmitter from cholinergic terminals, or is it mediated by noncholinergic nerves?
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Seven male and two female subjects participated in one or more of the protocols. Their average age (±SEM) was 29±3 years; average height, 172±3 cm; and average weight, 71±3 kg. All subjects were in good health, and their informed consent was obtained before their participation in these institutionally approved studies.
In protocols 1 and 3, whole-body heat stress was produced as follows: Subjects wore a tube-lined suit that was used to control Tsk by perfusion with water of different temperatures.19 20 Over the suit, subjects wore a water-impermeable plastic garment. 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°C to 39°C during heating periods or perfused with cold water to lower Tsk from a range of 34°C to 34.5°C to a range of 31.5°C to 32°C for cold stress.
Internal temperature was monitored from the esophagus (Tes).19 Tsk was recorded as the weighted electrical average from six thermocouples placed over the body surface.19 20 Heart rate was monitored continuously from the ECG. Mean arterial pressure was recorded continuously from a finger blood pressure monitor (Finapres, Ohmeda).
LDF from skin, assessed by dual-channel flowmeter (MBF3D, Moor Instruments Ltd), and SR, assessed by relative humidity monitors (HX92V, Omega Engineering; IH3602-L humidity sensors, HY-CAL Engineering), were measured simultaneously at each of two forearm sites. CVC was indexed as LDF (in volts)÷mean arterial pressure (in millimeters of mercury).
We constructed special LDF probe holders to permit simultaneous measurement of LDF and SR with concomitant control of local temperature at the site of LDF measurement. The LDF probe head was placed in a central chamber in the probe holder and was slightly raised from the skin surface. Dry air was passed through the central chamber and conducted to a relative humidity detector to measure SR. Local warming was accomplished by heating elements embedded within the probe holder. A thermocouple was placed between the skin surface and the probe holder to provide measurement of local temperature and feedback for temperature control.
In protocol 1, we characterized the role of cholinergic muscarinic receptors in cutaneous active vasodilation and sweating by investigating the effects of locally applied atropine, a cholinergic muscarinic receptor antagonist. Atropine sulfate was iontophoretically applied at a dose of 400 µA per cm2 for 45 seconds to a 0.64-cm2 area of forearm skin to block cutaneous cholinergic receptors in those areas. By local application, we could test the blocking effects of atropine, uncomplicated by any systemic effects. We then simultaneously monitored SkBF by laser-Doppler flowmetry21 22 and SR by relative humidity at the atropine-treated site and at an adjacent untreated site during periods of body heating and cooling. Body heating was used to produce heat stress and thus served to activate the vasodilator system. Body cooling was used to produce cold stress to test for intact noradrenergic vasoconstrictor function and thus to examine for unanticipated effects of atropine iontophoresis.
Data collection began with a 5-minute normothermic control period followed by a 3-minute application of whole-body cold stress to verify that vasoconstrictor nerve function was intact and that atropine pretreatment had not produced unanticipated effects on either nerve or vascular function. After a few minutes of recovery, Tsk was raised to 38°C to 39°C and was maintained at that level for 35 to 45 minutes to induce heat stress. After hyperthermia, subjects were cooled to normothermia. Local temperatures at both LDF sites were raised to 42°C for maximal vasodilation.23 24 For data analysis, values of CVC were normalized to those maximal levels.25
The vasomotor responses to cold stress and heat stress were analyzed by comparing the levels of CVC at treated and untreated sites during the initial control period with the levels achieved during the final minute of cold stress and heat stress. The sudomotor responses to heat stress were analyzed by comparing the level of SR during the initial control period with that achieved during the final minute of heat stress. Internal temperature thresholds (the level of Tes at which CVC or SR began to rise during whole-body heating) were chosen from plots of CVC or SR versus Tes by an investigator blinded to the conditions, subjects, and drug treatments involved. CVC, SR, and Tes responses were analyzed by ANOVA followed by the Student-Newman-Keuls test.
In protocol 2, atropine was applied by iontophoresis at one forearm site at the same current and duration as in protocol 1. Subjects were then placed in a supine position and instrumented at the treated site with a laser-Doppler probe equipped with a probe holder that provided for simultaneous LDF measurement, iontophoresis, and local warming. This probe holder contained a recessed plastic iontophoresis chamber with a platinum electrode. The chamber was filled with a solution of ACh in propylene glycol. The LDF probe head was placed in the holder and was slightly raised from the skin surface. Local warming was accomplished by resistors with thermocouple feedback. This enabled the monitoring of LDF while ACh was being applied. Blood pressure was measured as described above. Eight of the nine subjects participated in this protocol.
The protocol began with a 5-minute control period. ACh was then iontophoretically applied at a dose of 31 µA per cm2 for 45 seconds to the 0.64-cm2 area of forearm skin previously treated with atropine. Responses to ACh were monitored for 10 minutes, and then the local temperature at the forearm site was raised to 42°C for maximal vasodilation. The LDF probe was then moved to an untreated control site on the forearm, and the protocol was repeated. The responses of CVC at the two sites were analyzed by ANOVA followed by the Student-Newman-Keuls test.
Protocol 3 involved presynaptic cholinergic nerve blockade with local intradermal injection of botulinum toxin type A (Allergan Pharmaceuticals). This is an anticholinergic agent that is taken up selectively by presynaptic cholinergic nerve terminals, where it abolishes release of ACh and any colocalized neurotransmitters.26 Each of six subjects had a 0.6-cm2 area of skin on the ventral surface of the forearm injected intradermally with 5 U botulinum toxin. Two to 14 days after injection, during which cholinergic nerve blockade developed, we tested the effects of this blockade on LDF and SR at the area of forearm skin pretreated with botulinum toxin and at an adjacent untreated site. The study design and analysis used in protocol 3 were otherwise identical to those used in protocol 1.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fig 1
shows the time course of results from
protocol 1 in one subject. During cold stress, CVC fell from an average
of 18±2% to 12±1% of the maximal level at untreated sites
(P<.05) and from 19±2% to 14±2% of the maximal level at
atropine-treated sites (P<.05). These responses were
not different from each other (P>.10) and demonstrated that
atropine iontophoresis had not altered either the adrenergic
vasoconstrictor system or the responsiveness of the cutaneous vessels
themselves.
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During heat stress, no sweating was detected at sites pretreated with atropine. The value of Tes at which vasodilation began at the atropine-treated sites was slightly greater than that at the untreated sites (37.22±0.06°C [atropine-treated sites] and 37.14±0.06°C [untreated sites], P<.05). Despite total abolition of sweating by atropine treatment, CVC rose significantly at treated sites during heat stress. At the peak of heat stress, CVC had increased to 67±6% of the maximal level at untreated sites and to 50±6% of the maximal level at atropine-treated sites (P<.05 both sites). However, this vasodilation at atropine-treated sites was reduced in relation to that at control sites (P<.05 between sites). No differences were found in the absolute LDF values achieved with local warming at the two sites (P>.05 between sites). This indicated that atropine pretreatment had not altered the cutaneous vascular response to local warming and validated the normalization of CVC values to maximal levels.
In the second protocol, iontophoresis of ACh was used to exclude the
possibility that the foregoing results were due to an inadequate
blockade of muscarinic receptors on the cutaneous arterioles and to
test for a nonmuscarinic cholinergic vasodilation. The results from one
subject are illustrated in Fig 2. In response to ACh,
CVC at untreated control sites rose from 16±1% to 51±4% of the
maximal level (P<.05), whereas at sites pretreated with
atropine, CVC was unchanged by ACh (14±1% to 17±3% of the maximal
level, P>.05). These responses were significantly different
(P<.05 between sites).
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The third protocol involved presynaptic cholinergic nerve blockade with
local intradermal injection of botulinum toxin type A. Typical results
are shown in Fig 3. During cold stress, CVC fell from an
average of 10±2% to 7±1% of the maximal level at untreated sites
and from 10±1% to 7±1% of the maximal level at botulinum
toxin–treated sites (P<.05 at each site,
P>.10 between sites), demonstrating that botulinum toxin
had not altered the noradrenergic mediation of the
vasoconstrictor response to whole-body cooling. With heat stress,
sweating occurred at untreated sites but not at botulinum
toxin–treated sites, verifying cholinergic nerve blockade.
Simultaneously, CVC rose to 52±9% of the maximal level at
untreated sites (P<.05 versus control) but was not
significantly different from control levels at botulinum
toxin–treated sites (17±2% of the maximal level,
P>.05 versus control). Finally, no differences were found
in the absolute LDF values achieved during local warming to 42°C at
the two sites (P>.05 between sites). This indicated that
botulinum toxin pretreatment had not altered the cutaneous vascular
response to local warming and therefore again validated the
normalization of CVC values to maximal levels.
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Overall responses to hyperthermia and to cold stress in protocols 1 and
3 are summarized in Fig 4. The CVC responses to cold
stress were similar between the two protocols and were not affected by
atropine or botulinum toxin. However, presynaptic blockade of
cholinergic function (botulinum) abolished CVC increases during heat
stress, whereas postsynaptic antagonism only slightly reduced the CVC
response.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The results of the present study show that cutaneous active vasodilation in humans is mediated by cholinergic nerve cotransmission. This conclusion follows from the following observations: muscarinic blockade does not abolish cutaneous active vasodilation during heat stress, muscarinic receptor blockade abolishes the cutaneous vasodilation induced by exogenous ACh, and selective presynaptic cholinergic nerve blockade with botulinum toxin abolishes the active vasodilator response to hyperthermia.
The results of the first protocol showed that iontophoresis of atropine did not alter the vasoconstrictor responses to cold stress. Therefore, atropine iontophoresis did not measurably alter the cutaneous vasculature through nonmuscarinic effects. Atropine did abolish sweating during heat stress but failed to abolish the cutaneous vasodilation. Thus, most of the vasodilator response in CVC at atropine-treated sites is not mediated by activation of muscarinic receptors either on sweat glands or on the cutaneous vessels themselves.
The foregoing results could have been due to an inadequate blockade of muscarinic receptors on the cutaneous arterioles, despite complete blockade of the sweat glands. Alternatively, nonmuscarinic cholinergic receptors not subject to blockade by atropine, such as nicotinic receptors, could mediate cutaneous active vasodilation. These possibilities were examined in our second protocol. ACh treatment increased CVC at control sites to levels comparable to those achieved during heat stress but had no effect on CVC at sites pretreated with atropine. The failure of ACh iontophoresis to increase CVC at sites pretreated with atropine indicates that muscarinic receptors on the vessels themselves were adequately blocked and thus could not mediate active vasodilation. These results also demonstrate that muscarinic receptors are the only cholinergic receptors of functional importance in the cutaneous vasculature and that, therefore, cutaneous active vasodilation cannot be mediated by activation of nonmuscarinic cholinergic receptors.
As previously mentioned, the neurotransmitter of the vasodilator nerves is unknown, although an indirect relation to cholinergic sudomotor nerve activity has been postulated.2 3 Atropine locally abolished sudomotor but not vasomotor responses to hyperthermia. Thus, our results show that activation of the sweat glands is not necessary for active vasodilation and do not support a role for glandular production of kininogenase leading to bradykinin as the mechanism of active vasodilation.
From the results of protocols 1 and 2, we concluded that ACh is not the major mediator of cutaneous active vasodilation. The remaining issue regarding the role of cholinergic nerves in active vasodilation was the possibility of corelease of another neurotransmitter from cholinergic nerves as proposed by Hökfelt et al17 and Lundberg.27 According to this proposal, a single set of neurons could control both active vasodilation of cutaneous arterioles and sweating by coreleasing both ACh and VIP. In this scheme, ACh would control sweating, and coreleased VIP would cause active vasodilation.17 This colocalization mechanism could explain why atropine blocks sweating but inconsistently affects active vasodilation. In the third protocol, we used presynaptic cholinergic nerve blockade with local intradermal injection of botulinum toxin type A to test the possibility that cotransmitter release was involved in cutaneous active vasodilation. Botulinum toxin is an anticholinergic agent that is taken up selectively by presynaptic cholinergic nerve terminals.26 Within the nerve terminal, the toxin cleaves several proteins required for Ca+2-induced exocytosis, leading to total inhibition of this process.28 Abolition of Ca+2-induced exocytosis blocks release of small synaptic vesicles that contain ACh and large dense-core vesicles that mainly contain peptides.26 28 We reasoned that botulinum toxin would thus concomitantly abolish the release of any cotransmitters from cholinergic nerve endings that are secreted by Ca+2-induced exocytosis.26 28 The fact that vasoconstrictor function in the present study was unimpaired testifies to the selectivity of the action of botulinum toxin. Furthermore, it is not thought to affect the function of nonadrenergic noncholinergic nerves.26
Botulinum toxin locally abolished both the active vasodilator and sudomotor responses to hyperthermia. From this result, we conclude that activation of cholinergic nerves mediates cutaneous active vasodilation. Given the selectivity of botulinum toxin for cholinergic nerve terminals and our observations from protocols 1 and 2 that active cutaneous vasodilation is not mediated by activation of cholinergic receptors, these findings indicate that release of a cotransmitter from cholinergic nerves is the major mechanism of cutaneous active vasodilation.
VIP is considered the likely transmitter responsible for atropine-resistant vasodilation with parasympathetic nerve stimulation in the salivary gland.29 Is VIP the cotransmitter that causes cutaneous active vasodilation in humans? Probably not. Savage et al18 found active vasodilation to be normal in patients with cystic fibrosis, a group with very low VIP levels in postganglionic neurons. This finding suggests that VIP is not the specific cotransmitter of cutaneous active vasodilation in humans, although it appears to have a cotransmitter role elsewhere.17 27 Is nitric oxide the cotransmitter that mediates active vasodilation? This also appears unlikely. Dietz et al11 found that intra-arterial L-NMMA did not abolish cutaneous active vasodilation.11 This finding suggests that nitric oxide does not mediate cutaneous active vasodilation in humans. We have tried to iontophoretically deliver L-NMMA into the skin to investigate the role of nitric oxide but found that this could not be done because of problems with the iontophoretic application itself.
One local factor important to the cutaneous circulation is the temperature of the blood vessels themselves. Botulinum toxin did not alter the vasodilation induced by local warming of the skin to 42°C. This indicates that cholinergic nerves do not mediate the vasodilation induced by increased local temperature. Prior work from our laboratory found that the effects of local warming on cutaneous arterioles do not require intact adrenergic function and may involve an axon reflex.30 The results of the present study suggest that the vascular effects of increased local temperature do not involve cholinergic neurotransmission and thus are mediated by a mechanism separate from active vasodilation.
As mentioned previously, atropine was not without effect on the cutaneous vasodilation induced by heat stress. During hyperthermia, a small delay in the onset of cutaneous vasodilation occurred at atropine-treated sites (P<.05 between sites). In addition, the extent of vasodilation was slightly reduced by atropine (P<.05 between sites). These results are similar to previous findings based on intra-arterial infusions of atropine.14 A delayed and slightly reduced vasodilation at atropine-treated sites suggests that activation of muscarinic receptors participates in the increase of CVC during hyperthermia. It is possible that ACh contributes partially to cutaneous active vasodilation through postsynaptic muscarinic receptors on the skin vessels and that atropine eliminates that component. It is also conceivable that the reduction in vasodilation is limited to those vessels that only subserve sweat glands. Perhaps sweat gland activation by muscarinic receptors effects a local periglandular hyperemia that contributes to the vasodilation of heat stress. According to this hypothesis, increases in SkBF during heat stress are the sum of increased blood flow at cutaneous arterioles by the cotransmitter and the hyperemia of sweat gland activation by ACh. In addition to postsynaptic effects, ACh may have influences through presynaptic muscarinic autoreceptors that exert negative feedback on release of both ACh and the cotransmitter.27 Atropine blockade of such autoreceptors could lead to increased release of the cotransmitter. Increased cotransmitter release could mask the effect of postsynaptic muscarinic blockade and restore most of the vasodilation that was prevented by atropine.
In summary, we found that muscarinic receptor blockade with atropine did not abolish cutaneous active vasodilation during heat stress but did abolish the vasodilation induced by ACh. Presynaptic blockade of cholinergic nerves with botulinum toxin selectively abolished the active vasodilation induced by heat stress. Collectively, these results show that cutaneous active vasodilation is mediated by cholinergic nerves and indicate that the mechanism of cutaneous active vasodilation involves a cotransmitter released from those nerves. Identification of this cotransmitter and establishing whether these cholinergic nerves are identical with sudomotor nerves represent future challenges to understanding the mechanism of cutaneous active vasodilation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by an American Federation for Aging Research/Merck Fellowship in Geriatric Clinical Pharmacology (Dr Kellogg); National Heart, Lung, and Blood Institute grants HL-36080 (Dr Johnson) and HL-08861 (Dr Crandall); and a NATO grant through the German Academic Exchange Service (Dr Grossmann). The authors gratefully acknowledge Moor Instruments for their generous loan of an MBF3D laser-Doppler blood flow monitor and the volunteers for their participation and cooperation.
Received April 27, 1995; accepted August 2, 1995.
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 G. J. Hodges, D. N. Jackson, L. Mattar, J. M. Johnson, and J. K. Shoemaker Neuropeptide Y and neurovascular control in skeletal muscle and skin Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R546 - R555. [Abstract] [Full Text] [PDF]
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 C. D. Johnson, D. Melanaphy, A. Purse, S. A. Stokesberry, P. Dickson, and A. V. Zholos Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1868 - H1877. [Abstract] [Full Text] [PDF]
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 M. Shibasaki, P. Rasmussen, N. H. Secher, and C. G. Crandall Neural and non-neural control of skin blood flow during isometric handgrip exercise in the heat stressed human J. Physiol., May 1, 2009; 587(9): 2101 - 2107. [Abstract] [Full Text] [PDF]
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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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M. J. Joyner Cutaneous blood flow: uncomfortable in our own skin? Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H29 - H30. [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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J. Gonzalez-Alonso, C. G. Crandall, and J. M. Johnson The cardiovascular challenge of exercising in the heat J. Physiol., January 1, 2008; 586(1): 45 - 53. [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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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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G. H. Simmons, C. T. Minson, J.-L. Cracowski, and J. R. Halliwill Systemic hypoxia causes cutaneous vasodilation in healthy humans J Appl Physiol, August 1, 2007; 103(2): 608 - 615. [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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 V. B. Wyller, K. Godang, L. Morkrid, J. P. Saul, E. Thaulow, and L. Walloe Abnormal Thermoregulatory Responses in Adolescents With Chronic Fatigue Syndrome: Relation to Clinical Symptoms Pediatrics, July 1, 2007; 120(1): e129 - e137. [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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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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M. Shibasaki, S. L. Davis, J. Cui, D. A. Low, D. M. Keller, S. Durand, and C. G. Crandall Neurally mediated vasoconstriction is capable of decreasing skin blood flow during orthostasis in the heat-stressed human J. Physiol., September 15, 2006; 575(3): 953 - 959. [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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M. Shibasaki, T. E. Wilson, and C. G. Crandall Neural control and mechanisms of eccrine sweating during heat stress and exercise J Appl Physiol, May 1, 2006; 100(5): 1692 - 1701. [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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B. L. Houghton, J. R. Meendering, B. J. Wong, and C. T. Minson Nitric oxide and noradrenaline contribute to the temperature threshold of the axon reflex response to gradual local heating in human skin J. Physiol., May 1, 2006; 572(3): 811 - 820. [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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 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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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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J. M. Johnson, T. C. Yen, K. Zhao, and W. A. Kosiba Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1573 - H1579. [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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Y.-I. Kamijo, K. Lee, and G. W. Mack Active cutaneous vasodilation in resting humans during mild heat stress J Appl Physiol, March 1, 2005; 98(3): 829 - 837. [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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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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S. Golay, C. Haeberli, A. Delachaux, L. Liaudet, P. Kucera, B. Waeber, and F. Feihl Local heating of human skin causes hyperemia without mediation by muscarinic cholinergic receptors or prostanoids J Appl Physiol, November 1, 2004; 97(5): 1781 - 1786. [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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D. O. Warner, M. J. Joyner, and N. Charkoudian Nicotine increases initial blood flow responses to local heating of human non-glabrous skin J. Physiol., September 15, 2004; 559(3): 975 - 984. [Abstract] [Full Text] [PDF]
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P. Boutsiouki and G. F. Clough Modulation of microvascular function following low-dose exposure to the organophosphorous compound malathion in human skin in vivo J Appl Physiol, September 1, 2004; 97(3): 1091 - 1097. [Abstract] [Full Text] [PDF]
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D. P. Stephens, A. R. Saad, L. A. T. Bennett, W. A. Kosiba, and J. M. Johnson Neuropeptide Y antagonism reduces reflex cutaneous vasoconstriction in humans Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1404 - H1409. [Abstract] [Full Text] [PDF]
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 L. M. Peltonen and A. Pyornila Local action of exogenous nitric oxide (NO) on the skin blood flow of rock pigeons (Columba livia) is affected by acclimation and skin site J. Exp. Biol., July 1, 2004; 207(15): 2611 - 2619. [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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N. Toda and T. Okamura The Pharmacology of Nitric Oxide in the Peripheral Nervous System of Blood Vessels Pharmacol. Rev., June 1, 2003; 55(2): 271 - 324. [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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B. W Wilkins, L. A Holowatz, B. J Wong, and C. T Minson Nitric oxide is not permissive for cutaneous active vasodilatation in humans J. Physiol., May 1, 2003; 548(3): 963 - 969. [Abstract] [Full Text] [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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J. M. Pierzga, A. Frymoyer, and W. L. Kenney Delayed distribution of active vasodilation and altered vascular conductance in aged skin J Appl Physiol, March 1, 2003; 94(3): 1045 - 1053. [Abstract] [Full Text] [PDF]
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F. M. Paro, M. C. Almeida, E. C. Carnio, and L. G. S. Branco Role of L-glutamate in systemic AVP-induced hypothermia J Appl Physiol, January 1, 2003; 94(1): 271 - 277. [Abstract] [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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 C. G. Crandall, W. Vongpatanasin, and R. G. Victor Cocaine and Body Temperature Regulation Ann Intern Med, November 19, 2002; 137(10): 855 - 856. [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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N. Charkoudian, A. Vella, A. S. Reed, C. T. Minson, P. Shah, R. A. Rizza, and M. J. Joyner Cutaneous vascular function during acute hyperglycemia in healthy young adults J Appl Physiol, October 1, 2002; 93(4): 1243 - 1250. [Abstract] [Full Text] [PDF]
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C. G. Crandall, W. Vongpatanasin, and R. G. Victor Mechanism of Cocaine-Induced Hyperthermia in Humans Ann Intern Med, June 4, 2002; 136(11): 785 - 791. [Abstract] [Full Text] [PDF]
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 J. Pleiner, E. Heere-Ress, H. Langenberger, A. E. Sieder, M. Bayerle-Eder, F. Mittermayer, G. Fuchsjager-Mayrl, J. Bohm, B. Jansen, and M. Wolzt Adrenoceptor Hyporeactivity Is Responsible for Escherichia coli Endotoxin-Induced Acute Vascular Dysfunction in Humans Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 95 - 100. [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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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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C. T. Minson, L. T. Berry, and M. J. Joyner Nitric oxide and neurally mediated regulation of skin blood flow during local heating J Appl Physiol, October 1, 2001; 91(4): 1619 - 1626. [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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 M. Lepori, C. Sartori, H. Duplain, P. Nicod, and U. Scherrer Interaction between cholinergic and nitrergic vasodilation: a novel mechanism of blood pressure control Cardiovasc Res, September 1, 2001; 51(4): 767 - 772. [Abstract] [Full Text] [PDF]
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N. Charkoudian, B. Fromy, and J.-L. Saumet Reflex control of the cutaneous circulation after acute and chronic local capsaicin J Appl Physiol, May 1, 2001; 90(5): 1860 - 1864. [Abstract] [Full Text] [PDF]
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D. P. Stephens, K. Aoki, W. A. Kosiba, and J. M. Johnson Nonnoradrenergic mechanism of reflex cutaneous vasoconstriction in men Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1496 - H1504. [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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Y. Nakajima, T. Mizobe, A. Takamata, and Y. Tanaka Baroreflex modulation of peripheral vasoconstriction during progressive hypothermia in anesthetized humans Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2000; 279(4): R1430 - R1436. [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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 L. Kovács, T. Török, F. Bari, Z. Kéri, A. Kovács, E. Makula, and G. Pokorny Impaired microvascular response to cholinergic stimuli in primary Sjogren's syndrome Ann Rheum Dis, January 1, 2000; 59(1): 48 - 53. [Abstract] [Full Text]
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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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 T. Okamura, K. Ayajiki, M. Uchiyama, M. Uehara, and N. Toda Neurogenic Vasodilatation of Canine Isolated Small Labial Arteries J. Pharmacol. Exp. Ther., March 1, 1999; 288(3): 1031 - 1036. [Abstract] [Full Text]
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D. L. Kellogg Jr., C. G. Crandall, Y. Liu, N. Charkoudian, and J. M. Johnson Nitric oxide and cutaneous active vasodilation during heat stress in humans J Appl Physiol, September 1, 1998; 85(3): 824 - 829. [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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D. L. Kellogg Jr., S. R. Morris, S. B. Rodriguez, Y. Liu, M. Grossmann, G. Stagni, and A. M. M. Shepherd Thermoregulatory reflexes and cutaneous active vasodilation during heat stress in hypertensive humans J Appl Physiol, July 1, 1998; 85(1): 175 - 180. [Abstract] [Full Text] [PDF]
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M. J. Joyner and N. M. Dietz Nitric oxide and vasodilation in human limbs J Appl Physiol, December 1, 1997; 83(6): 1785 - 1796. [Abstract] [Full Text] [PDF]
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M. J. Joyner Invited Editorial on "Nitric oxide and thermoregulation during exercise in the horse" J Appl Physiol, April 1, 1997; 82(4): 1033 - 1034. [Full Text] [PDF]
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