Skip to main content
NCBI home page
Journal of Applied Physiology logoLink to Journal of Applied Physiology
. 2009 Feb;106(2):571–575. doi: 10.1152/japplphysiol.91249.2008

Effect of elevated local temperature on cutaneous vasoconstrictor responsiveness in humans

Jonathan E Wingo 1,2, David A Low 1, David M Keller 1,2, R Matthew Brothers 1, Manabu Shibasaki 3, Craig G Crandall 1,2
PMCID: PMC3313836  PMID: 19056996

Abstract

Cutaneous vascular conductance (CVC) increases in response to local skin heating. Although attenuation of vasoconstrictor responsiveness due to local heating has been demonstrated, the mechanism(s) responsible for this attenuation remains unclear. Nitric oxide has been shown to at least partially contribute to this response, but other mechanisms also may be involved. The purpose of this study was to test the hypothesis that local heating diminishes cutaneous vasoconstrictor responsiveness through a nitric oxide-independent mechanism by altering postsynaptic reactivity to norepinephrine. A follow-up protocol tested the hypothesis that local heating attenuates the presynaptic release of neurotransmitters that cause vasoconstriction, also via non-nitric oxide mechanisms. In protocol I, CVC was assessed in eight subjects during administration of increasing doses of norepinephrine (via intradermal microdialysis) at adjacent sites separately heated to 34°C and 40°C. In protocol II, which was identical to, but separate from, protocol I, CVC was assessed in seven subjects during administration of increasing doses of tyramine, which causes release of neurotransmitters from adrenergic nerves. At each site for both protocols, nitric oxide synthesis was inhibited (via microdialysis administration of NG-nitro-l-arginine methyl ester) and flow was matched (via microdialysis administration of adenosine); therefore, temperature was the only variable that differed between the sites. For both protocols, nonlinear regression analysis revealed no difference (P > 0.05) in the effective drug concentration causing 50% of the vasoconstrictor response. Minimum CVC [6.3 ± 2.0 and 9.0 ± 4.0% of peak CVC (mean ± SD) for protocol I and 19.3 ± 9.3 and 20.5 ± 11.9% of peak CVC for protocol II at 34°C and 40°C sites, respectively] was not different between sites. Independent of nitric oxide, local skin heating to 40°C does not attenuate adrenergically mediated cutaneous vasoconstriction through pre- or postsynaptic mechanisms.

Keywords: nitric oxide, skin temperature, microdialysis, norepinephrine, tyramine

in humans, heat stress increases cutaneous vascular conductance (CVC) as a result of withdrawal of vasoconstrictor neural activity, engagement of a sympathetic active vasodilator system, and direct effects of increased local temperature (12). Local temperature can increase when ambient temperature surpasses skin temperature and/or when humidity is high and sweating becomes less efficient in removing heat from the skin (19).

During pronounced heat stress, cardiac output can increase to 7 l/min over resting baseline, with the potential for distribution of ≥50% of total cardiac output to the skin (22, 23). This elevated CVC can present a challenge to blood pressure regulation, especially if orthostasis is combined with heat stress (15, 30). The precise mechanism by which heat stress impairs orthostatic tolerance is incompletely understood, but it may be related to increased local skin temperature, since local heating attenuates cutaneous vasoconstriction elicited by lower body negative pressure (16), at the onset of exercise (26), and during administration of exogenous norepinephrine (29). Consistent with human data, elevated local temperature reduces adrenergic responsiveness in isolated canine vessel preparations (4, 28).

It is unclear how local heating interferes with cutaneous vasoconstriction. Cutaneous vasodilation during sustained local heating is primarily dependent on nitric oxide (13, 17), which has been shown to attenuate cutaneous vasoconstrictor responsiveness (6, 11, 24, 25, 33), but it is unclear whether nitric oxide is solely responsible for diminished cutaneous vasoconstriction associated with local heating. Non-nitric oxide mechanisms, such as differences in skin blood flow between locally heated and nonheated sites (29) and differences in temperature per se (16), may contribute to local heating attenuation of cutaneous vasoconstriction.

The purpose of this study was to test the hypothesis that elevated temperature attenuates cutaneous vasoconstrictor responsiveness, through pre- and postsynaptic mechanisms, when nitric oxide and baseline skin blood flow are controlled.

METHODS

Subjects.

Subjects were free of any known cardiovascular, metabolic, or neurological diseases. Eight individuals (4 women and 4 men) participated in protocol I, and seven individuals (3 women and 4 men) participated in protocol II. Their age, height, and weight (means ± SD) were 38 ± 10 yr, 172.0 ± 8.8 cm, and 77.9 ± 16.2 kg for protocol I and 38 ± 13 yr, 178.5 ± 6.2 cm, and 77.5 ± 12.0 kg for protocol II. There was no control for phase of the menstrual cycle. The study was approved by the Institutional Review Boards at the University of Texas Southwestern Medical Center at Dallas and Presbyterian Hospital of Dallas, and subjects provided written informed consent before enrolling in the study.

Instrumentation.

For both protocols, subjects rested supine during placement of microdialysis membranes (Bioanalytical Systems, West Lafayette, IN) at four sites in posterior forearm skin. Each membrane was perfused with lactated Ringer solution (Baxter, Deerfield, IL) at a rate of 2 μl/min via a perfusion pump (Harvard Apparatus, Holliston, MA). On the skin above the membrane, each site was instrumented with a local heater (model PF 450, Perimed, North Royalton, OH) covering ∼7 cm2 and a laser-Doppler flow probe (model DP7a, Moor Instruments, Wilmington, DE) housed in the local heater for measurement of skin blood flow. A thermocouple (type T, Omega Engineering, Stamford, CT) was placed between the skin and the local heater to monitor local skin temperature. Arterial blood pressure was obtained intermittently using electrosphygmomanometry of the brachial artery (Tango, SunTech Medical Instruments, Raleigh, NC).

Procedures for protocol I.

After instrumentation, sodium nitroprusside (SNP) was administered for ∼15–20 min through the microdialysis membranes to elicit peak cutaneous vasodilation at each site. After SNP administration, membranes were perfused with lactated Ringer solution for ∼2–2.5 h while skin blood flow returned to pre-SNP baseline levels. In the first few subjects, 50 mM SNP was administered to elicit peak cutaneous vasodilation, but an inordinately long time was required for skin blood flow to return to baseline following cessation of SNP administration. Consequently, in subsequent subjects, 28 mM SNP was administered to elicit peak cutaneous vasodilation, while reducing the time required for skin blood flow to return to baseline. This latter concentration of SNP has been shown to cause maximal vasodilation in the cutaneous vasculature (13, 18, 31). The nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 10 mM) was then administered at all sites. This concentration of l-NAME has been shown to inhibit nitric oxide synthase to the same extent as higher doses (18). Two sites were then locally heated to 34°C and the other two sites were locally heated to 40°C, while l-NAME continued to be perfused through all sites. When CVCs at 34°C and 40°C sites were closely matched (within ∼10 %CVCpeak units) across all four sites, data from the two 34°C sites were averaged and compared with data averaged from the two 40°C sites. Otherwise, data from the site locally heated to 34°C that most closely matched data from the site locally heated to 40°C (within ∼10 %CVCpeak units) were selected for analysis. Once skin blood flow was stable at all sites, 5.6 mM adenosine + 10 mM l-NAME was perfused through all membranes to match skin blood flow, by nitric oxide-independent mechanisms, between sites at 34°C and sites at 40°C. Once skin blood flow stabilized, progressively increasing doses of norepinephrine (from 1 × 10−8 to 1 × 10−2 M in 1 × 10−1 M increments) were administered. On passage of the new dose through the “dead space” of the microdialysis probe, thereby ensuring that the new dose was at the membrane, each dose of norepinephrine was administered for 5 min at a perfusion rate of 2 μl/min. Throughout norepinephrine administration, sites continued to receive 5.6 mM adenosine + 10 mM l-NAME.

Procedures for protocol II.

Given the findings from protocol I, a follow-up protocol was conducted to determine whether local heating altered vasoconstrictor responsiveness via a presynaptic mechanism. The procedures for protocol II were identical to those for protocol I with the following exceptions. After sites were locally heated, 5.6 mM adenosine + 10 mM l-NAME was perfused through the sites locally heated at 34°C while a slightly lower concentration of adenosine (2.8 mM) + 10 mM l-NAME was perfused through the sites locally heated at 40°C, thus improving the matching of CVCs between sites relative to protocol I. Similar to protocol I, if CVCs at both 34°C sites were within 10 %CVCpeak units at the 40°C sites, then CVCs for the respective temperature sites were averaged, and these averaged values were statistically evaluated. If this was not the case, then CVCs at the 34°C site that most closely matched CVC at the 40°C site (also within ∼10 %CVCpeak units) were statistically compared. After skin blood flow stabilized, progressively increasing doses of tyramine (from 1 × 10−7 to 1 × 10−2 M in 1 × 10−1 M increments) were administered to all sites for 6 min per dose at a perfusion rate of 2 μl/min to cause the release of neurotransmitters, including norepinephrine, from sympathetic adrenergic nerve endings. Similar to protocol I, sites continued to receive adenosine + 10 mM l-NAME throughout tyramine administration.

Data analysis.

Data from both protocols were analyzed similarly, so the following procedure pertains to the entire data set. Data were acquired continuously at a sampling rate of 50 Hz using a data acquisition system (Biopac, Santa Barbara, CA). Data from the final minute of each dose of drug were averaged and analyzed. CVC was calculated as the ratio of arbitrary skin blood flux units to mean arterial pressure and normalized to responses achieved during peak cutaneous vasodilation via SNP administration (%CVCpeak). In protocol I, data were collected from 11 subjects, but data from 3 individuals were excluded for the following reasons: in 2 subjects, CVCs at 34°C and 40°C sites differed by >15 %CVCpeak units, and 1 subject did not respond to norepinephrine, probably because of failure of the microdialysis membrane. In protocol II, eight subjects completed the study, but one subject was excluded because of failure to respond to tyramine. CVC data were mathematically modeled using nonlinear regression curve fitting (Prism, GraphPad, San Diego, CA), and dose-response curves for percent CVCpeak were generated. The model identified the effective drug concentration causing 50% of the maximal vasoconstrictor response (EC50), as well as the lowest percent CVCpeak values achieved during drug administration. Data from each site (34°C vs. 40°C) derived from the model were then compared using paired-samples t-tests. Additional data analysis included a two-way (site × dose) repeated-measures ANOVA to compare local skin temperature between sites across drug doses as well as percent CVCpeak at each site for each dose of the respective drug. Values are means ± SD. P < 0.05 was considered statistically significant.

RESULTS

Procotol I.

Local heating elicited average skin temperatures of 34.31 ± 0.31°C and 39.72 ± 0.55°C at the 34°C and 40°C sites, respectively, across all drug doses (main effect of site, P < 0.001). Administration of adenosine was moderately successful in matching percent CVCpeak between sites before norepinephrine administration (44.2 ± 18.0% and 51.4 ± 21.0% for 34°C and 40°C sites, respectively, P = 0.054). Nonlinear regression curve fitting for the norepinephrine dose response had high goodness of fit at the 34°C (mean R2 = 0.99 ± 0.01) and 40°C (mean R2 = 0.98 ± 0.01) sites (P = 0.57 between sites; Fig. 1). There were no differences between sites (P > 0.05) for either of the parameters derived from the model [Fig. 1; EC50 (log norepinephrine concentration) = −5.2 ± 0.7 and −4.7 ± 0.5 at 34°C and 40°C sites, respectively, and lowest %CVCpeak = 6.3 ± 2.0 and 9.0 ± 4.0 at 34°C and 40°C sites, respectively], indicating that a given dose of norepinephrine caused a similar degree of vasoconstriction at each site. Similarly, the ANOVA assessing percent CVCpeak between sites across each dose of norepinephrine did not reveal a significant interaction (P = 0.09), thereby further indicating that the thermal status of the site did not affect the responsiveness to norepinephrine.

Fig. 1.

Fig. 1.

Open in a new tab

Dose-response relationships of percent peak cutaneous vascular conductance (CVCpeak) to norepinephrine administration ([norepinephrine]) in protocol I at sites locally heated to 34°C and 40°C. Local heating to 40°C had no effect on cutaneous vasoconstrictor responsiveness characterized by the lowest percent CVCpeak in response to norepinephrine administration (P = 0.09 between sites) or effective norepinephrine concentration causing 50% of the vasoconstrictor response (P = 0.11 between sites). Values are means ± SD.

Protocol II.

Because of the absence of an effect of local temperature on postsynaptic vasoconstrictor responsiveness outlined in protocol I, protocol II was adopted to evaluate the hypothesis that elevated local temperature attenuates the release of neurotransmitters that cause cutaneous vasoconstriction. Skin temperature averaged 34.43 ± 0.33°C at the 34°C site and 39.96 ± 0.25°C at the 40°C site, and this difference was maintained across all doses of tyramine (main effect of site, P < 0.001). Similar to protocol I, administration of adenosine was sufficient to match percent CVCpeak between sites before tyramine administration (39.0 ± 21.6% and 43.3 ± 24.1% for 34°C and 40°C sites, respectively, P = 0.14). Goodness of fit from the nonlinear regression model was high for each site (mean R2 = 0.95 ± 0.05 and 0.92 ± 0.07 for 34°C and 40°C sites, respectively, P = 0.46 between sites; Fig. 2). Local heating did not alter the EC50 for tyramine (−3.9 ± 0.5 and −3.6 ± 0.4 log norepinephrine concentration for 34°C and 40°C sites, respectively, P = 0.11), nor were there differences between sites for the minimum percent CVCpeak derived from the model (19.3 ± 9.3 and 20.5 ± 11.9% CVCpeak for 34°C and 40°C sites, respectively, P = 0.49). As with protocol I, there was no significant interaction between sites and dose of tyramine for percent CVCpeak (P = 0.41).

Fig. 2.

Fig. 2.

Open in a new tab

Dose-response relationship of percent CVCpeak to tyramine administration in protocol II at sites locally heated to 34°C and 40°C. Local heating to 40°C had no effect on presynaptic release of catecholamines responsible for vasoconstriction, via tyramine administration, as evidenced by similar minimum percent CVCpeak (P = 0.49 between sites) and similar effective tyramine concentrations causing 50% of the vasoconstrictor response (P = 0.11 between sites). Values are means ± SD.

DISCUSSION

The purpose of this study was to identify whether local temperature, independent of nitric oxide and potential differences in skin blood flow, attenuates cutaneous vasoconstrictor responsiveness through postsynaptic inhibition of norepinephrine-mediated vasoconstriction and/or through altered presynaptic release of stored neurotransmitters responsible for vasoconstriction (i.e., norepinephrine and, perhaps, cotransmitters, such as neuropeptide Y). We measured cutaneous blood flow responses to exogenous norepinephrine (to assess postsynaptic inhibition of α-adrenergic stimulation) and tyramine (given the results of protocol I, to assess possible attenuation of neurotransmitter release from adrenergic nerves) at sites locally heated to different temperatures while skin blood flow between sites was matched and nitric oxide synthase was inhibited. The primary finding from this study is that local heating to ∼40°C did not alter cutaneous vasoconstrictor responsiveness to exogenous norepinephrine in the absence of nitric oxide or different baseline skin blood flows. Furthermore, presynaptic release of noradrenergic neurotransmitters was not impaired by local heating, as evidenced by similar CVC responses to tyramine at 34°C and 40°C sites.

The lack of attenuation of cutaneous vasoconstrictor responsiveness at sites locally heated to 40°C in the present study is in contrast to the findings from a previous study in which we reported that local heating to ≥37°C attenuates cutaneous vasoconstrictor responsiveness to exogenous norepinephrine compared with a site maintained at 34°C (29). However, a primary limitation of our previous study was the absence of matched skin blood flow among sites heated from 34°C to 42°C. Thus, differences in skin blood flow between sites, not local temperature, may have been the primary mechanism resulting in attenuated vasoconstrictor responsiveness at the ≥37°C sites relative to the 34°C control site. This line of thinking is consistent with the literature highlighting the importance of the initial baseline in evaluating vascular responses (11, 20). For example, greater vasodilation, and hence higher skin blood flow, associated with greater local temperature, introduces uncontrolled variables, such as nitric oxide release associated with increased shear stress. In the study of Wilson et al. (29), such uncontrolled variables cloud the interpretation of whether local temperature per se attenuates vasoconstrictor responsiveness in human skin.

Another difference between the present study and that of Wilson et al. (29) is the absence of control for nitric oxide production between sites heated to different temperatures. Since nitric oxide has been demonstrated to impair vasoconstriction in animal models (9, 10, 14, 33), in human skeletal muscle (5), and in human skin (6, 11, 24, 25), attenuated cutaneous vasoconstriction between sites heated to different local temperatures in the study of Wilson et al. may have been due to the influence of varying concentrations of nitric oxide.

Nitric oxide may not be the most important component of local heating that attenuates cutaneous vasoconstriction, as evidenced by data reported by Low et al. (16). They compared the reduction of CVC in response to lower body negative pressure at sites with different local temperatures. Four skin sites were initially heated to 34°C for 15 min. Lactated Ringer solution was administered at two control sites and 10 mM l-NAME was administered at the other two sites for 10 min. Then lower body negative pressure at 60 mmHg was applied for 5 min. After 5 min of recovery, two of the sites were heated to 39°C and the other two sites were heated to 42°C. Lactated Ringer solution was administered at one site at each temperature to serve as a control, while adenosine + 10 mM l-NAME was administered at the other site at each temperature that had been treated with l-NAME during heating to 34°C. Then lower body negative pressure at 60 mmHg was applied for 5 min. The decrease in CVC during lower body negative pressure was smaller at the sites heated to 42°C than at those heated to 39°C, while the decrease in CVC at the 39°C sites was similar to the decrease at the sites with temperature clamped at 34°C. However, for a given local temperature (e.g., 39°C or 42°C), there were no differences in the magnitude of the decrease in CVC between sites that received l-NAME and those that did not receive l-NAME. This observation suggests that nitric oxide may not be the primary mechanism impairing cutaneous vasoconstrictor responsiveness during local heating. Nevertheless, the independent effects of local temperature on cutaneous vasoconstrictor responsiveness were not isolated in the study of Low et al. (16) or the study of Wilson et al. (29), since skin blood flow was not controlled between sites heated to different local temperatures. Thus the present study was performed to evaluate the effects of local skin temperature, independent of skin blood flow and nitric oxide, on pre- and postsynaptic vasoconstrictor responsiveness.

Studies focusing on cold-induced vasoconstriction may offer insight into the mechanisms behind the current findings. Since human and animal studies have shown reduced adrenergic transmitter release in conjunction with reduced local temperature (3, 7), the potentiation of smooth muscle contraction responsible for vasoconstriction during local cooling has been attributed to alteration in location (1, 2, 27) and/or affinity of α2-adrenergic receptors (7). The absence of differences in vasoconstrictor responsiveness between sites heated to 34°C and those heated to 40°C in the present study suggests that, in contrast to local cooling, local heating does not reduce adrenergic transmitter release and/or does not interfere with the translocation or affinity of α2-adrenoceptors.

For the present study, local temperature was elevated to 40°C, whereas local heating to 42°C is commonly performed to elicit maximal cutaneous vasodilation. A local temperature of 40°C, instead of 42°C, was selected, because it was not possible to consistently match CVC at the 34°C site with CVC achieved at a 42°C site via non-nitric oxide mechanisms (i.e., with a coinfusion of l-NAME). Had 42°C local heating been employed in the present study, CVC would have been substantially higher than CVC at the 34°C site. We therefore cannot exclude the possibility that, with local heating above 40°C, cutaneous vasoconstrictor responsiveness is impaired as a result of temperature alone (i.e., independent of skin blood flow and nitric oxide).

Although percent CVCpeak did not differ significantly between the sites (P = 0.054), percent CVCpeak before drug administration was 7 units higher at the site heated to 40°C, which may be physiologically meaningful. Nevertheless, the minimum percent CVCpeak derived from the nonlinear regression model, as well as the EC50 values, were not different between sites. This observation supports the conclusion that vasoconstrictor responsiveness is not reduced at the site heated to 40°C, despite an elevated (albeit nonstatistically different) percent CVCpeak at this site before norepinephrine administration.

Perspectives

It is recognized that local skin temperatures of ∼40°C are not likely encountered under ordinary daily activities, except when environmental temperature is elevated when humidity is high or evaporation of sweat is impeded or abolished (e.g., when nuclear, biological, and chemical protective suits are worn). The basis for evaluating such a high local skin temperature was to maximize the potential effect of elevated local temperature on cutaneous vasoconstrictor responsiveness. Since no effect was observed, it is unlikely that local skin temperatures, independent of skin blood flow and nitric oxide, below the applied level (i.e., in a more physiological range) attenuate cutaneous vasoconstrictor responsiveness.

Elevated skin temperature, albeit typically <40°C, commonly occurs during heat stress. For example, in high-ambient-temperature environments, skin temperature can reach ≥37°C (8, 21, 32). This information, coupled with prior work suggesting that local heating attenuates cutaneous vasoconstrictor responsiveness (16, 25, 26, 29), provides a possible mechanism by which orthostatic tolerance is reduced in heat-stressed individuals (15, 30). The present data demonstrate that attenuated blood pressure control in subjects with elevated skin blood flow, secondary to local heating, is not the result of elevated local temperature per se (at least at skin temperature ≤40°C) but, rather, a yet to be identified effect of that elevated local temperature.

In summary, local heating of skin to 40°C in the absence of nitric oxide and with matched skin blood flow had no effect on cutaneous vasoconstrictor responsiveness to exogenous norepinephrine administration compared with local clamping of skin temperature at 34°C. Similarly, presynaptic release of neurotransmitters that cause vasoconstriction, stimulated by tyramine, also was not affected by local heating to 40°C compared with 34°C. Attenuation of cutaneous vasoconstrictor responsiveness associated with local heating is not due to an independent effect of elevated local temperature. Future studies are needed to determine the mechanisms, occurring in conjunction with local heating, that may be responsible for attenuated cutaneous vasoconstrictor responsiveness.

GRANTS

This project was funded by National Institutes of Health Grants HL-61388, HL-84072, and GM-68865.

Acknowledgments

We thank Amanda Fralin, Jena Porterfield, and Kim Hubing for technical assistance.

Current affiliations: D. A. Low, Centre for Sports Medicine and Human Performance, Brunel University, Uxbridge, Middlesex, UK; D. M. Keller, Department of Kinesiology, University of Texas at Arlington, Arlington, TX 76019.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

REFERENCES

  • 1.Bailey SR, Eid AH, Mitra S, Flavahan S, Flavahan NA. Rho kinase mediates cold-induced constriction of cutaneous arteries: role of α2C-adrenoceptor translocation. Circ Res 94: 1367–1374, 2004. [DOI] [PubMed] [Google Scholar]
  • 2.Bailey SR, Mitra S, Flavahan S, Flavahan NA. Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol 289: H243–H250, 2005. [DOI] [PubMed] [Google Scholar]
  • 3.Boels PJ, Verbeuren TJ, Vanhoutte PM. Moderate cooling depresses the accumulation and the release of newly synthesized catecholamines in isolated canine saphenous veins. Experientia 41: 1374–1377, 1985. [DOI] [PubMed] [Google Scholar]
  • 4.Cooke JP, Shepherd JT, Vanhoutte PM. The effect of warming on adrenergic neurotransmission in canine cutaneous vein. Circ Res 54: 547–553, 1984. [DOI] [PubMed] [Google Scholar]
  • 5.Costa F, Christensen NJ, Farley G, Biaggioni I. NO modulates norepinephrine release in human skeletal muscle: implications for neural preconditioning. Am J Physiol Regul Integr Comp Physiol 280: R1494–R1498, 2001. [DOI] [PubMed] [Google Scholar]
  • 6.Durand S, Davis SL, Cui J, Crandall CG. Exogenous nitric oxide inhibits sympathetically mediated vasoconstriction in human skin. J Physiol 562: 629–634, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Flavahan NA The role of vascular α2-adrenoceptors as cutaneous thermosensors. News Physiol Sci 6: 251–255, 1991. [Google Scholar]
  • 8.Fox RH, Goldsmith R, Hampton IF, Hunt TJ. Heat acclimatization by controlled hyperthermia in hot-dry and hot-wet climates. J Appl Physiol 22: 39–46, 1967. [DOI] [PubMed] [Google Scholar]
  • 9.Greenberg SS, Diecke FP, Peevy K, Tanaka TP. Release of norepinephrine from adrenergic nerve endings of blood vessels is modulated by endothelium-derived relaxing factor. Am J Hypertens 3: 211–218, 1990. [DOI] [PubMed] [Google Scholar]
  • 10.Habler HJ, Wasner G, Janig W. Attenuation of neurogenic vasoconstriction by nitric oxide in hindlimb microvascular beds of the rat in vivo. Hypertension 30: 957–961, 1997. [DOI] [PubMed] [Google Scholar]
  • 11.Hodges GJ, Kosiba WA, Zhao K, Alvarez GE, Johnson JM. The role of baseline in the cutaneous vasoconstrictor responses during combined local and whole body cooling in humans. Am J Physiol Heart Circ Physiol 293: H3187–H3192, 2007. [DOI] [PubMed] [Google Scholar]
  • 12.Johnson JM, Proppe DW. Cardiovascular adjustments to heat stress. In: Handbook of Physiology. Environmental Physiology. Bethesda, MD: Am. Physiol. Soc., 1996, sect. 4, vol. I, chapt. 11, p. 215–243. [Google Scholar]
  • 13.Kellogg DL, Liu Y, Kosiba IF, O'Donnell D. Role of nitric oxide in the vascular effects of local warming of the skin in humans. J Appl Physiol 86: 1185–1190, 1999. [DOI] [PubMed] [Google Scholar]
  • 14.Kolo LL, Westfall TC, Macarthur H. Nitric oxide decreases the biological activity of norepinephrine resulting in altered vascular tone in the rat mesenteric arterial bed. Am J Physiol Heart Circ Physiol 286: H296–H303, 2004. [DOI] [PubMed] [Google Scholar]
  • 15.Lind AR, Leithead CS, McNicol GW. Cardiovascular changes during syncope induced by tilting men in the heat. J Appl Physiol 25: 268–276, 1968. [DOI] [PubMed] [Google Scholar]
  • 16.Low DA, Shibasaki M, Davis SL, Keller DM, Crandall CG. Does local heating-induced nitric oxide production attenuate vasoconstrictor responsiveness to lower body negative pressure in human skin? J Appl Physiol 102: 1839–1843, 2007. [DOI] [PubMed] [Google Scholar]
  • 17.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. [DOI] [PubMed] [Google Scholar]
  • 18.Minson CT, Holowatz LA, Wong BJ, Kenney WL, Wilkins BW. Decreased nitric oxide- and axon reflex-mediated cutaneous vasodilation with age during local heating. J Appl Physiol 93: 1644–1649, 2002. [DOI] [PubMed] [Google Scholar]
  • 19.Nadel ER, Stolwijk AJ. Effect of skin wettedness on sweat gland response. J Appl Physiol 35: 689–694, 1973. [DOI] [PubMed] [Google Scholar]
  • 20.O'Leary DS Regional vascular resistance vs. conductance: which index for baroreflex responses? Am J Physiol Heart Circ Physiol 260: H632–H637, 1991. [DOI] [PubMed] [Google Scholar]
  • 21.Piwonka RW, Robinson S. Acclimatization of highly trained men to work in severe heat. J Appl Physiol 22: 9–12, 1967. [DOI] [PubMed] [Google Scholar]
  • 22.Rowell LB Circulatory adjustments to dynamic exercise and heat stress: competing controls. In: Human Circulation: Regulation During Physical Stress. New York: Oxford University Press, 1986, p. 363–406.
  • 23.Rowell LB, Brengelmann GL, Murray JA. Cardiovascular responses to sustained high skin temperature in resting man. J Appl Physiol 27: 673–680, 1969. [DOI] [PubMed] [Google Scholar]
  • 24.Shibasaki M, Durand S, Davis SL, Cui J, Low DA, Keller DM, Crandall CG. Endogenous nitric oxide attenuates neutrally-mediated cutaneous vasoconstriction. J Physiol 585: 627–634, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Shibasaki M, Low DA, Davis SL, Crandall CG. Nitric oxide inhibits cutaneous vasoconstriction to exogenous norepinephrine. J Appl Physiol 105: 1504–1508, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Taylor WF, Johnson JM, O'Leary DS, Park MK. Modification of the cutaneous vascular response to exercise by local skin temperature. J Appl Physiol 57: 1878–1884, 1984. [DOI] [PubMed] [Google Scholar]
  • 27.Thompson-Torgerson CS, Holowatz LA, Flavahan NA, Kenney WL. Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin. Am J Physiol Heart Circ Physiol 292: H1700–H1705, 2007. [DOI] [PubMed] [Google Scholar]
  • 28.Vanhoutte PM, Shepherd JT. Effect of temperature on reactivity of isolated cutaneous veins of the dog. Am J Physiol 218: 187–190, 1970. [DOI] [PubMed] [Google Scholar]
  • 29.Wilson TE, Cui J, Crandall CG. Effect of whole-body and local heating on cutaneous vasoconstrictor responses in humans. Auton Neurosci 97: 122–128, 2002. [DOI] [PubMed] [Google Scholar]
  • 30.Wilson TE, Cui J, Zhang R, Witkowski S, Crandall CG. Skin cooling maintains cerebral blood flow velocity and orthostatic tolerance during tilting in heated humans. J Appl Physiol 93: 85–91, 2002. [DOI] [PubMed] [Google Scholar]
  • 31.Wong BJ, Wilkins BW, Holowatz LA, Minson CT. Nitric oxide synthase inhibition does not alter the reactive hyperemic response in the cutaneous circulation. J Appl Physiol 95: 504–510, 2003. [DOI] [PubMed] [Google Scholar]
  • 32.Wyndham CH, Rogers GG, Senay LC, Mitchell D. Acclimization in a hot, humid environment: cardiovascular adjustments. J Appl Physiol 40: 779–785, 1976. [DOI] [PubMed] [Google Scholar]
  • 33.Zanzinger J, Czachurski J, Seller H. Inhibition of sympathetic vasoconstriction is a major principle of vasodilation by nitric oxide in vivo. Circ Res 75: 1073–1077, 1994. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Applied Physiology are provided here courtesy of American Physiological Society

RESOURCES