Cutaneous Active Vasodilation Research Articles

Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans

Human skin blood flow responses to body heating and cooling are essential to the normal processes of physiological thermoregulation. Large increases in skin blood flow provide the necessary augmentation of convective heat loss during environmental heat exposure and/or exercise, just as reflex cutaneous vasoconstriction is key to preventing excessive heat dissipation during cold exposure. In humans, reflex sympathetic innervation of the cutaneous circulation has two branches: a sympathetic noradrenergic vasoconstrictor system, and a non-noradrenergic active vasodilator system. Noradrenergic vasoconstrictor nerves are tonically active in normothermic environments and increase their activity during cold exposure, releasing both norepinephrine and cotransmitters (including neuropeptide Y) to decrease skin blood flow. The active vasodilator system in human skin does not exhibit resting tone and is only activated during increases in body temperature, such as those brought about by heat exposure or exercise. Active cutaneous vasodilation occurs via cholinergic nerve cotransmission and has been shown to include potential roles for nitric oxide, vasoactive intestinal peptide, prostaglandins, and substance P (and/or neurokinin-1 receptors). It has proven both interesting and challenging that no one substance has been identified as the sole mediator of active cutaneous vasodilation. The processes of reflex cutaneous vasodilation and vasoconstriction are both modified by acute factors, such as exercise and hydration, and more long-term factors, such as aging, reproductive hormones, and disease. This review will highlight some of the recent findings in these areas, as well as interesting areas of ongoing and future work.

ATP Does Not Mitigate Adrenergically-Mediated Vasoconstriction in Human Skin

Unknown factors associated with active cutaneous vasodilation have the capacity to attenuate adrenergically-mediated cutaneous vasoconstriction. Adenosine triphosphate (ATP) is reputedly co-released from sympathetic cholinergic nerves, which are the nerves responsible for cutaneous active vasodilation. In skeletal muscle, ATP inhibits adrenergically-mediated vasoconstriction. Therefore, ATP may be responsible for attenuating cutaneous vasoconstriction upon engagement of the cutaneous active vasodilator system. The effect of ATP on cutaneous vasoconstriction remains unknown, however. PURPOSE: To test the hypothesis that ATP inhibits adrenergically-mediated cutaneous vasoconstriction. METHODS: Four microdialysis probes were inserted in dorsal forearm skin of 11 healthy individuals (mean ± SD; 35 ± 11 years). Local temperature at each site was clamped at 34 °C throughout the protocol. Skin blood flux was measured by laser-Doppler flowmetry and was used to calculate cutaneous vascular conductance (CVC; skin blood flux/mean arterial pressure), which was later normalized to peak CVC achieved with sodium nitroprusside infusion combined with local skin heating to ∼42 °C. Two microdialysis probes were perfused with 30 mM ATP while the other 2 were flow matched via administration of 2.8 mM adenosine to serve as control sites. After achieving stable baselines, adrenergically-mediated cutaneous vasoconstriction was induced by administration of 1·10-4 M tyramine at all sites while ATP and adenosine continued to be infused at their respective sites. RESULTS: Administration of tyramine decreased CVC ∼34% at all sites (P<0.001), but the magnitude of decrease was not different between sites (P=0.32 for interaction). CONCLUSIONS: These findings indicate that unlike in skeletal muscle, ATP does not attenuate adrenergically-mediated vasoconstriction in human skin. Supported by NIH Grants HL61388 & HL84072.

VIP/PACAP receptor mediation of cutaneous active vasodilation during heat stress in humans

Vasoactive intestinal peptide (VIP) is implicated in cutaneous active vasodilation in humans. VIP and the closely related pituitary adenylate cyclase activating peptide (PACAP) act through several receptor types: VIP through VPAC1 and VPAC2 receptors and PACAP through VPAC1, VPAC2, and PAC1 receptors. We examined participation of VPAC2 and/or PAC1 receptors in cutaneous vasodilation during heat stress by testing the effects of their specific blockade with PACAP6-38. PACAP6-38 dissolved in Ringer's was administered by intradermal microdialysis at one forearm site while a control site received Ringer's solution. Skin blood flow was monitored by laser-Doppler flowmetry (LDF). Blood pressure was monitored noninvasively and cutaneous vascular conductance (CVC) calculated. A 5- to 10-min baseline period was followed by approximately 70 min of PACAP6-38 (100 microM) perfusion at one site in normothermia and a 3-min period of body cooling. Whole body heating was then performed to engage cutaneous active vasodilation and was maintained until CVC had plateaued at an elevated level at all sites for 5-10 min. Finally, 58 mM sodium nitroprusside was perfused through both microdialysis sites to effect maximal vasodilation. No CVC differences were found between control and PACAP6-38-treated sites during normothermia (19 +/- 3%max untreated vs. 20 +/- 3%max, PACAP6-38 treated; P > 0.05 between sites) or cold stress (11 +/- 2%max untreated vs. 10 +/- 2%max, PACAP6-38 treated, P > 0.05 between sites). PACAP6-38 attenuated the increase in CVC during whole body heating when compared with untreated sites (59 +/- 3%max untreated vs. 46 +/- 3%max, PACAP6-38 treated, P < 0.05). We conclude that VPAC2 and/or PAC1 receptor activation is involved in cutaneous active vasodilation in humans.

VPAC2 And/Or PAC1 Receptors Interact with NOS during Heat Stress in Humans

VPAC2 and/or PAC1 receptors are implicated in cutaneous active vasodilation(AVD) during heat stress(HS). Nitric oxide(NO) from NOS also plays important roles in HS in humans. We hypothesized that NO and VPAC2/PAC1 interact in AVD during HS. We examined this interaction by testing the effects of specific blockade of these receptors with and without NOS inhibition during HS. The VPAC2/PAC1 antagonist, Pituitary Adenylate Cyclase Activating Peptide 6‐38(PACAP6‐38) and the NOS inhibitor, L‐NAME(LNM) were used. PACAP6‐38, LNM, a combination(MIX) of PACAP6‐38 and LNM, or Ringer's solution alone were perfused at 4 separate intradermal microdialysis sites. Skin blood flow(SkBF) was monitored by aser‐Doppler flowmetry and body temperature controlled with water‐perfused suits. The protocol began with a 10 minute baseline period without antagonist perfusion. This was followed by 45 minutes of PACAP6‐38, L‐NM or Mix perfusion at respective site in normothermia(Norm). Norm was followed by a 3‐minute period of whole body cooling (CS). Whole body heating was then performed to effect HS and activate AVD. After HS, 58mM sodium nitroprusside was perfused at all MD sites to effect maximal vasodilation for data normalization. No differences were found between Ringer's and PACAP6‐38, L‐NAME, or MIX sites during Norm(p&gt;0.05 among sites) or CS(p&gt;0.05 among sites). All three treated sites attenuated AVD in HS when compared to Ringer's sites(p&lt;0.05). Greater attenuation occurred at LNM and MIX sites than in PACAP6‐38 sites(p&lt;0.05); however, AVD attenuation was not different between LNM and MIX treated sites(P&gt;0.05, LNM vs MIX). We conclude that VPAC2/PAC1 receptors interact with NO during AVD. (supported by NIH Grant HL065599)

Plasma hyperosmolality elevates the internal temperature threshold for active thermoregulatory vasodilation during heat stress in humans

Plasma hyperosmolality delays the response in skin blood flow to heat stress by elevating the internal temperature threshold for cutaneous vasodilation. This elevation could be because of a delayed onset of cutaneous active vasodilation and/or to persistent cutaneous active vasoconstriction. Seven healthy men were infused with either hypertonic (3% NaCl) or isotonic (0.9% NaCl) saline and passively heated by immersing their lower legs in 42 degrees C water for 60 min (room temperature, 28 degrees C; relative humidity, 40%). Skin blood flow was monitored via laser-Doppler flowmetry at sites pretreated with bretylium tosylate (BT) to block sympathetic vasoconstriction selectively and at adjacent control sites. Plasma osmolality was increased by approximately 13 mosmol/kgH(2)O following hypertonic saline infusion and was unchanged following isotonic saline infusion. The esophageal temperature (T(es)) threshold for cutaneous vasodilation at untreated sites was significantly elevated in the hyperosmotic state (37.73 +/- 0.11 degrees C) relative to the isosmotic state (36.63 +/- 0.12 degrees C, P < 0.001). A similar elevation of the T(es) threshold for cutaneous vasodilation was observed between osmotic conditions at the BT-treated sites (37.74 +/- 0.18 vs. 36.67 +/- 0.07 degrees C, P < 0.001) as well as sweating. These results suggest that the hyperosmotically induced elevation of the internal temperature threshold for cutaneous vasodilation is due primarily to an elevation in the internal temperature threshold for the onset of active vasodilation, and not to an enhancement of vasoconstrictor activity.

Soluble Guanylyl Cyclase and Cutaneous Active Vasodilation During Heat Stress in Humans

Nitric oxide(NO) dependent systems typically involve cGMP generation via NO activation of soluble guanylyl cyclase(sGC) as a step in vasodilation. We hypothesized this mechanism participates in cutaneous active vasodilation(AVD) during whole body heat stress(HS). We examined effects of a specific sGC inhibitor, ODQ, on AVD during HS. 3 intradermal microdialysis probes(MD) were inserted into forearm skin in 7 subjects. Skin blood flow was monitored by Laser‐Doppler Flowmetry(LDF). Body temperature was controlled with water‐perfused suits. Blood pressure was monitored by Finapres and cutaneous vascular conductance calculated(CVC=LDF/MAP). The study began with perfusion of Ringer's at all sites, followed by 2%DMSO in Ringer's or 1mM ODQ dissolved in 2%DMSO/Ringer's at 2 separate MD sites. (Preliminary studies showed that 1mMODQ antagonized NO mediated vasodilation by sodium nitroprusside.) Ringer's was continuously perfused at the 3rd control site(CTR). The protocol began with 40 minutes of normothermia followed by 3 minutes of cold stress(CS) after which whole body heating was performed to effect HS and activate AVD. After HS, 58mM SNP was perfused through all MD sites to maximally vasodilate for data normalization.Resultsthere were no differences between sites during normothermia. No differences were found between sites in normothermia or CS. There was no significant difference between Ringer's and DMSO sites at the peak of HS on CVC. ODQ tended to attenuate the maximal CVC achieved at the peak of HS(p=0.0536 vs CTR and DMSO). Blockade sGC by ODQ tended to attenuate AVD during HS, these data suggest that sGC activation participates in AVD.

About “Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilatation in middle-aged humans”

LETTERS TO THE EDITORAbout “Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilatation in middle-aged humans”G. Mahe, P. Rousseau, J. L. Saumet, and P. AbrahamG. Mahe, P. Rousseau, J. L. Saumet, and P. AbrahamPublished Online:01 Apr 2009https://doi.org/10.1152/japplphysiol.91653.2008MoreSectionsPDF (27 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat to the editor: We read with much interest the article by Holowatz and Kenney (3) entitled “Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilatation in middle-aged humans.” The authors showed that chronic aspirin therapy (81 mg/day) plays a major role in the reflex cutaneous vasodilatation induced by whole body heating. This result is consistent with those reported by McCord et al. (4) that showed that the cyclooxygenase-dependent (COX) pathway was participating in the cutaneous vasodilatation induced by whole body heating but not by local heating. Vasodilatation induced by local heating relies on an axon-reflex for the early response and on a nitric oxide (NO)-dependent pathway for the late part of the response (5). On the contrary, vasodilatation induced by whole body heating depends on the NO pathway and the COX pathway but not on an axon-reflex (1, 3). The whole body heating is an interesting experimental model to study physiological responses during heat waves. Heat waves are an important health problem. Heat waves were estimated directly or indirectly to be responsible for ∼70,000 elderly deaths in Europe in 2003. Many elderly subjects take low-dose aspirin (<325 mg/day) as an effective therapy in prevention of cardiovascular diseases. As whole body heat-induced vasodilatation depends on the COX pathway even at low dose as shown by Holowatz and Kenney, do we need to stop low-dose aspirin therapy during heat waves? Other antiplatelet drugs exist (such as ADP inhibitors). We showed that the current-induced vasodilatation (CIV), another model of skin vasodilatation, was COX dependent(2) but not ADP dependent (6). Whether the whole body heating model is ADP dependent is an important issue. If not, rather than stop aspirin, should we recommend the use of antiplatelet drugs other than aspirin during heat waves? Future studies are likely needed to investigate this important clinical issue.REFERENCES1 Charkoudian N, Fromy B, Saumet JL. Reflex control of the cutaneous circulation after acute and chronic local capsaicin. J Appl Physiol 90: 1860–1864, 2001.Link | ISI | Google Scholar2 Durand S, Fromy B, Bouye P, Saumet JL, Abraham P. Vasodilatation in response to repeated anodal current application in the human skin relies on aspirin-sensitive mechanisms. J Physiol 540: 261–269, 2002.Crossref | PubMed | ISI | Google Scholar3 Holowatz LA, Kenney WL. Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation in middle-aged humans. J Appl Physiol 106: 500–505, 2009.Link | ISI | Google Scholar4 McCord GR, Cracowski JL, Minson CT. Prostanoids contribute to cutaneous active vasodilation in humans. Am J Physiol Regul Integr Comp Physiol 291: R596–R602, 2006.Link | ISI | Google Scholar5 Minson CT, Berry LT, Joyner MJ. Nitric oxide and neurally mediated regulation of skin blood flow during local heating. J Appl Physiol 91: 1619–1626, 2001.Link | ISI | Google Scholar6 Rousseau P, Tartas M, Fromy B, Godon A, Custaud MA, Saumet JL, Abraham P. Platelet inhibition by low-dose aspirin but not by clopidogrel reduces the axon-reflex current-induced vasodilation in humans. Am J Physiol Regul Integr Comp Physiol 294: R1420–R1426, 2008.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: G. Mahe, Univ. Hospital, 4, Rue Larrey, 49000 Angers, France (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByReply to Mahe, Rousseau, Saumet, and AbrahamLacy A. Holowatz and W. Larry Kenney1 April 2009 | Journal of Applied Physiology, Vol. 106, No. 4 More from this issue > Volume 106Issue 4April 2009Pages 1471-1471 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.91653.2008PubMed19336681History Published online 1 April 2009 Published in print 1 April 2009 Metrics

VPAC1 And / Or PAC1 Receptors Participate in Cutaneous Active Vasodilation during Heat Stress in Humans

Vasoactive Intestinal Peptide (VIP) has been implicated in cutaneous active vasodilation (AVD) during heat stress in humans. Effects of VIP and related neuropeptides are mediated by several receptor types. We examined participation of VPAC1 and/or PAC1 receptors in cutaneous vasodilation during heat stress by testing the effects of specific blockade of these receptors on AVD. The VPAC1/PAC1 antagonist, Pituitary Adenylate Cyclase Activating Peptide 6–38 (PACAP 6–38) was administered by intradermal microdialysis. One site was treated with PACAP 6–38 through MD. The second site was perfused with Ringer's solution only. Skin blood flow (SkBF) was monitored by laser-Doppler flowmetry (LDF) at those sites. Body temperature was controlled with water-perfused suits. Blood pressure was monitored by Finapres and cutaneous vascular conductance calculated (CVC=LDF/MAP). The protocol began with 5 minute baseline period without PACAP 6–38 perfusion. This was followed by approximately 70 minutes of PACAP 6–38 perfusion at one site in normothermia. Normothermia was followed by a 3 minute period of whole body cooling (CS). Whole body heating was then performed to effect heat stress (HS) and activate AVD. After HS, 58mM sodium nitroprusside was perfused through both MD sites to effect maximal vasodilation for data normalization. No differences were found between Ringer's and PACAP 6–38 treated sites during normothermia (p>0.05 between sites) or cold stress (p>0.05 between sites). PACAP 6–38 attenuated the extent of AVD in HS when compared to untreated sites (p=0.05, n=6). We conclude that VPAC1 and/or PAC1 receptors play an important role in AVD in HS in humans. (supported by NIH Grant HL065599)

A quantitative assessment of skin blood flow in humans

Various aspects of skin blood flow (SkBF) in human beings have been studied experimentally for more than seven decades. While reasonably complete phenomenological descriptions of individual factors have emerged from those investigations, little effort has been devoted to assembling the component parts into a coherent description of the entire system. This paper describes an effort to do that. Although the result is essentially a mathematical model of human SkBF, the model is firmly based on empirical data and not merely an abstract theoretical construct. We found that experimental data for human forearm blood flow (FBF) from many sources are well represented by an equation in which the rate of cutaneous blood flow (q (s)) is defined by the equation q (s) = q (s,r) AVD x CVCM x CVCL x CVCE. The coefficient q (s,r) is the perfusion rate at a reference state, and the four component factors are defined as follows: AVD defines centrally mediated active vasodilation as a function of central temperature (T (c)), mean skin temperature (T(s))d intensity of exercise (V(o)(2)) CVCM defines reflexly mediated cutaneous vasoconstriction as a function of (T(s)) CVCL defines locally mediated cutaneous vasoconstriction as a function of local skin temperature (T (s)); and CVCE defines the effect of exercise on cutaneous vasoconstriction and mean arterial pressure. The definition of each component function is based on experimental data. Two conclusions are particularly significant. One is that the study provides a rational explanation, based on the role of (T(s)), for previously disparate opinions about the non-thermal effect of exercise on active cutaneous vasodilation. The other is that it establishes that the four factors combine multiplicatively, and not additively, as previous investigators have suggested.

In vivo vasodilating mechanisms: who's NOS involved?

appreciate the importance and difficulty of identifying cellular mechanisms in physiological conditions. Indeed, 7-NI was administrated by intradermal microdialysis (2 mm) allowing large local drug concentration with local effects at the site of administration and thus avoiding systemic effects. Data were normalized to the SNP-induced maximal vasodilatation performed at the end of each protocol. Changes in skin blood flow were monitored by laser‐Doppler flowmetry (LDF) that gives continuous beat-to-beat information specific to cutaneous microvascular perfusion in a non-invasive manner. LDF measurements provide a robust approach to evaluate mechanisms of microvascular dilatation and their modification by physiological perturbations. The study reported that during nNOS inhibition, the skin vasodilatation due to whole-body heating was attenuated (∼30%) in contrast to local skin heating. The authors demonstrated that, in vivo, the nNOS isoform is responsible for NO generation during centrally mediated, reflex cutaneous active vasodilatation in whole-body heating, but is not involved in increasing skin blood flow in response to axon reflex-mediated, local skin heating. This study also showed that the nNOS isoform generates NO from the very initial phase of cutaneous active vasodilatation and continues during prolonged whole-body heat stress. However, Kellogg et al. (2008) strongly suggest that NO acts to increase synergistically the vasodilating effects of other neurotransmitters rather than acting as a direct mediator of vasodilatation. Interestingly, they excluded any participation of eNOS in centrally mediated reflex cutaneous active vasodilatation since studies using l-NAME, a non-selective isoform NOS antagonist, reported approximately an identical attenuation of 30% of skin blood flow increases to that of 7-NI, a selective nNOS antagonist, highlighting the possibility that nNOS is the sole NOS

Endogenous nitric oxide attenuates neutrally mediated cutaneous vasoconstriction

Cutaneous vasoconstrictor responsiveness may be impaired by substance(s) directly or indirectly responsible for cutaneous active vasodilatation. In this study, we tested the hypothesis that endogenous nitric oxide (NO) attenuates the reduction in cutaneous vascular conductance (CVC) during an orthostatic challenge combined with whole-body heating, as well as during whole-body cooling. In protocol 1, healthy subjects were pretreated with an intradermal injection of botulinum toxin A (BTX) to block the release of neurotransmitters from nerves responsible for cutaneous active vasodilatation. On the experimental day, a microdialysis probe was placed at the BTX-treated site as well as at two adjacent untreated sites. NG-nitro-l-arginine methyl ester (L-NAME, 10 mm) was perfused through the probe placed at the BTX-treated site and at one untreated site. After confirmation of the absence of cutaneous vasodilatation at the BTX site during whole-body heating, adenosine was infused through the microdialysis probe at this site to increase skin blood flow to a level similar to that at the untreated site. Subsequently, 30 and 40 mmHg lower-body negative pressures (LBNPs) were applied. The reduction in CVC to LBNP was greatest at the BTX-treated site (15.0 +/- 2.4% of the maximum level (% max)), followed by the L-NAME-treated site (11.3 +/- 2.6% max), and then the untreated site (3.8 +/- 3.0% max; P < 0.05 for all comparisons). In protocol 2, two microdialysis membranes were inserted in the dermal space of one forearm. Adenosine alone was infused at one site while the other site received adenosine and L-NAME. The reduction in CVC in response to whole-body cooling was significantly greater at the L-NAME-treated site than at the adjacent adenosine alone site. These results suggest that endogenous NO is capable of attenuating cutaneous vasoconstrictor responsiveness.

Exogenous melatonin administration modifies cutaneous vasoconstrictor response to whole body skin cooling in humans

Humans and other diurnal species experience a fall in internal temperature (T(int)) at night, accompanied by increased melatonin and altered thermoregulatory control of skin blood flow (SkBF). Also, exogenous melatonin induces a fall in T(int), an increase in distal skin temperatures and altered control of the cutaneous active vasodilator system, suggesting an effect of melatonin on the control of SkBF. To test whether exogenous melatonin also affects the more tonically active vasoconstrictor system in glabrous and nonglabrous skin during cooling, healthy males (n = 9) underwent afternoon sessions of whole body skin temperature (T(sk)) cooling (water-perfused suits) after oral melatonin (Mel; 3 mg) or placebo (Cont). Cutaneous vascular conductance (CVC) was calculated from SkBF (laser Doppler flowmetry) and non-invasive blood pressure. Baseline T(int) was lower in Mel than in Cont (P < 0.01). During progressive reduction of T(sk) from 35 degrees C to 32 degrees C, forearm CVC was first significantly reduced at T(sk) of 34.33 +/- 0.01 degrees C (P < 0.05) in Cont. In contrast, CVC in Mel was not significantly reduced until T(sk) reached 33.33 +/- 0.01 degrees C (P < 0.01). The decrease in forearm CVC in Mel was significantly less than in Cont at T(sk) of 32.66 +/- 0.01 degrees C and lower (P < 0.05). In Mel, palmar CVC was significantly higher than in Cont above T(sk) of 33.33 +/- 0.01 degrees C, but not below. Thus exogenous melatonin blunts reflex vasoconstriction in nonglabrous skin and shifts vasoconstrictor system control to lower T(int). It provokes vasodilation in glabrous skin but does not suppress the sensitivity to falling T(sk). These findings suggest that by affecting the vasoconstrictor system, melatonin has a causal role in the nocturnal changes in body temperature and its control.

Cholinergic mechanisms of cutaneous active vasodilation during heat stress in cystic fibrosis

To test the hypothesis that cutaneous active vasodilation in heat stress is mediated by a redundant cholinergic cotransmitter system, we examined the effects of atropine on skin blood flow (SkBF) increases during heat stress in persons with (CF) and without cystic fibrosis (non-CF). Vasoactive intestinal peptide (VIP) has been implicated as a mediator of cutaneous vasodilation in heat stress. VIP-containing cutaneous neurons are sparse in CF, yet SkBF increases during heat stress are normal. In CF, augmented ACh release or muscarinic receptor sensitivity could compensate for decreased VIP; if so, active vasodilation would be attenuated by atropine in CF relative to non-CF. Atropine was administered into skin by iontophoresis in seven CF and seven matched non-CF subjects. SkBF was monitored by laser-Doppler flowmetry (LDF) at atropine treated and untreated sites. Blood pressure [mean arterial pressure (MAP)] was monitored (Finapres), and cutaneous vascular conductance was calculated (CVC = LDF/MAP). The protocol began with a normothermic period followed by a 3-min cold stress and 30-45 min of heat stress. Finally, LDF sites were warmed to 42 degrees C to effect maximal vasodilation. CVC was normalized to its site-specific maximum. During heat stress, CVC increased in both CF and non-CF (P < 0.01). CVC increases were attenuated by atropine in both groups (P < 0.01); however, the responses did not differ between groups (P = 0.99). We conclude that in CF there is not greater dependence on redundant cholinergic mechanisms for cutaneous active vasodilation than in non-CF.

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

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

Neurokinin‐1 receptor desensitization attenuates cutaneous active vasodilatation in humans

To date, the neurotransmitter(s) and pathways involved in cutaneous active vasodilatation are not fully understood. The purpose of this study was to determine the potential involvement of neurokinin-1 (NK(1)) receptors to active vasodilatation. Our experimental model exploited our previous findings that repeated microdialysis infusions of substance P desensitize the NK(1) receptors and that substance P-induced vasodilatation contains a substantial nitric oxide (NO) component. Eleven subjects were equipped with four microdialysis fibres on the ventral forearm. Site 1 served as a control and received a continuous infusion of Ringer solution. Site 2 received a continuous infusion of 10 mM L-NAME to inhibit NO synthase. Site 3 received a 10 microm dose of substance P to desensitize the NK(1) receptors prior to whole-body heating. Site 4 received a 10 microm dose of substance P combined with 10 mM L-NAME. Red blood cell (RBC) flux was measured via laser-Doppler flowmetry, and cutaneous vascular conductance (CVC) was calculated as RBC flux/mean arterial pressure and normalized to maximal vasodilatation via 28 mM sodium nitroprusside. Substance P was infused for 15 min at 4 microl min(-1) in sites 3 and 4, and skin blood flow was allowed to return to baseline (approximately 45-60 min). Subjects then underwent a period of whole-body heat stress to raise oral temperature 0.8-1.0 degrees C above baseline. Pretreatment with substance P increased CVC to 48 +/- 2% CVC(max), which was significantly greater than for sites pretreated with substance P combined with L-NAME (27 +/- 2% CVC(max); P < 0.001). During whole-body heating, CVC in control sites increased to 69 +/- 3% CVC(max). Sites pretreated with substance P (48 +/- 3% CVC(max)) were significantly reduced compared to control sites (P < 0.001). The CVC response to whole-body heat stress in L-NAME sites was significantly reduced (32 +/- 3% CVC(max); P < 0.001) compared to both control sites and sites pretreated with substance P. The CVC response to whole-body heating was nearly abolished in sites pretreated with substance P combined with L-NAME (20 +/- 2% CVC(max)) and was significantly reduced compared to the other three sites (all P < 0.001). These data suggest NK(1) receptors contribute to active vasodilatation and that combined NK(1) receptor desensitization and NO synthase inhibition further diminishes active vasodilatation.

Neurally mediated vasoconstriction is capable of decreasing skin blood flow during orthostasis in the heat‐stressed human

Given the large increase in cutaneous vascular conductance (CVC) during whole-body heat stress, this vascular bed is important in the regulation of blood pressure during orthostatic stress. In this thermal state, changes in CVC are reported to be due to withdrawal of active vasodilator activity. The purpose of this study was to identify, contrary to the current line of thinking, whether cutaneous vasoconstrictor neural activity is enhanced and capable of contributing to reductions in CVC during an orthostatic challenge of heat-stressed individuals. Healthy normotensive subjects were pretreated, subcutaneously, with botulinum toxin A (BTX-A) to inhibit the release of neurotransmitters from cutaneous active vasodilator nerves. On the experimental day, microdialysis probes were placed in the BTX-A-treated site and in an adjacent untreated site. In protocol 1, internal temperature was elevated approximately 0.7 degrees C, followed by the application of lower body negative pressure (LBNP; -30 mmHg). LBNP reduced CVC at the BTX-A-treated sites (Delta4.2 +/- 2.9%max), as well as at the control site (Delta9.8 +/- 4.1%max). In protocol 2, after confirming the absence of cutaneous vasodilatation at the BTX-A-treated site during whole-body heating, CVC at this site was elevated to a similar level relative to the control site (55.4 +/- 13.4 versus 60.7 +/- 10.4%max, respectively) via intradermal administration of isoproterenol prior to LBNP. Similarly, when flow was matched between sites, LBNP reduced CVC at both the BTX-A-treated (Delta15.3 +/- 4.6%max) and the control sites (Delta8.8 +/- 5.6%max). These data suggest that the cutaneous vasoconstrictor system is engaged and is capable of decreasing CVC during an orthostatic challenge in heat-stressed individuals.

Prostanoids contribute to cutaneous active vasodilation in humans

The specific mechanisms by which skin blood flow increases in response to a rise in core body temperature via cutaneous active vasodilation are poorly understood. The primary purpose of this study was to determine whether the cyclooxygenase (COX) pathway contributes to active vasodilation during whole body heat stress (protocol 1; n = 9). A secondary goal was to verify that the COX pathway does not contribute to the cutaneous hyperemic response during local heating (protocol 2; n = 4). For both protocols, four microdialysis fibers were placed in forearm skin. Sites were randomly assigned and perfused with 1) Ringer solution (control site); 2) ketorolac (KETO), a COX-1/COX-2 pathway inhibitor; 3) NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor; and 4) a combination of KETO and L-NAME. During the first protocol, active vasodilation was induced using whole body heating with water-perfused suits. The second protocol used local heaters to induce a local hyperemic response. Red blood cell flux (RBC flux) was indexed at all sites using laser-Doppler flowmetry, and cutaneous vascular conductance (CVC; RBC flux/mean arterial pressure) was normalized to maximal vasodilation at each site. During whole body heating, CVC values at sites perfused with KETO (43 +/- 9% CVCmax), L-NAME (35 +/- 9% CVCmax), and combined KETO/L-NAME (22 +/- 8% CVCmax) were significantly decreased with respect to the control site (59 +/- 7% CVCmax) (P < 0.05). Additionally, CVC at the combined KETO/L-NAME site was significantly decreased compared with sites infused with KETO or L-NAME alone (P < 0.05). In the second protocol, the hyperemic response to local heating did not differ between the control site and KETO site or between the L-NAME and KETO/L-NAME site. These data suggest that prostanoids contribute to active vasodilation, but do not play a role during local thermal hyperemia.

Temperature control: from molecular insights, regulation in king penguins and diving seals, to studies in humans

more than 100 manuscripts have been submitted in response to the special call on “Physiology and Pharmacology of Temperature Regulation,” which required spreading publication of the manuscripts over several issues of the journal. Dr. Andrej Romanovsky serves as the Special Editor for this call

Modification of cutaneous vasodilator response to heat stress by daytime exogenous melatonin administration

In humans, the nocturnal fall in internal temperature is associated with increased endogenous melatonin and with a shift in the thermoregulatory control of skin blood flow (SkBF), suggesting a role for melatonin in the control of SkBF. The purpose of this study was to test whether daytime exogenous melatonin would shift control of SkBF to lower internal temperatures during heat stress, as is seen at night. Healthy male subjects (n = 8) underwent body heating with melatonin administration (Mel) or without (control), in random order at least 1 wk apart. SkBF was monitored at sites pretreated with bretylium to block vasoconstrictor nerve function and at untreated sites. Cutaneous vascular conductance, calculated from SkBF and arterial pressure, sweating rate (SR), and heart rate (HR) were monitored. Skin temperature was elevated to 38 degrees C for 35-50 min. Baseline esophageal temperature (Tes) was lower in Mel than in control (P < 0.01). The Tes threshold for cutaneous vasodilation and the slope of cutaneous vascular conductance with respect to Tes were also lower in Mel at both untreated and bretylium-treated sites (P < 0.05). The Tes threshold for the onset of sweating and the Tes for a standard HR were reduced in Mel. The slope of the relationship of HR, but not SR, to Tes was lower in Mel (P < 0.05). These findings suggest that melatonin affects the thermoregulatory control of SkBF during hyperthermia via the cutaneous active vasodilator system. Because control of SR and HR are also modified, a central action of melatonin is suggested.

Delayed Threshold for Active Cutaneous Vasodilation in Patients with Type 2 Diabetes Mellitus.

Wick, D E; Roberts, S K; Basu, A; Sandroni, P; Fealey, R D; Sletten, D; Charkoudian, N Author Information