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HIGHLIGHTED TOPIC
A Physiological Systems Approach to Human and Mammalian Thermoregulation

Relative roles of local and reflex components in cutaneous vasoconstriction during skin cooling in humans

Department of Physiology, The University of Texas Health Science Center, San Antonio, Texas

Submitted 3 October 2005 ; accepted in final form 12 February 2006

	ABSTRACT

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The reduction in skin blood flow (SkBF) with cold exposure is partly due to the reflex vasoconstrictor response from whole body cooling (WBC) and partly to the direct effects of local cooling (LC). Although these have been examined independently, little is known regarding their roles when acting together, as occurs in environmental cooling. We tested the hypothesis that the vasoconstrictor response to combined LC and WBC would be additive, i.e., would equal the sum of their independent effects. We further hypothesized that LC would attenuate the reflex vasoconstrictor response to WBC. We studied 16 (7 women, 9 men) young (30.5 ± 2 yr) healthy volunteers. LC and WBC were accomplished with metal Peltier cooler-heater probe holders and water-perfused suits, respectively. Forearm SkBF was monitored by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF/blood pressure. Subjects underwent 15 min of LC alone or 15 min of WBC with and without simultaneous LC, either at equal levels (34–31°C) or as equipotent stimuli (34–28°C LC; 34–31°C WBC). The fall in CVC with combined WBC and LC was greater (P < 0.05) than for either alone (57.0 ± 5% combined vs. 39.2 ± 6% WBC; 34.4 ± 4% LC) with equipotent cooling, but it was only significantly greater than for LC alone with equal levels of cooling (51.3 ± 8% combined vs. 29.5 ± 4% LC). The sum of the independent effects of WBC and LC was greater than their combined effects (74.9 ± 4 vs. 51.3 ± 8% equal and 73.6 ± 7 vs. 57.0 ± 5% equipotent; P < 0.05). The fall in CVC with WBC at LC sites was reduced compared with control sites (17.6 ± 2 vs. 42.4 ± 8%; P < 0.05). Hence, LC contributes importantly to the reduction in SkBF with body cooling, but also suppresses the reflex response, resulting in a nonadditive effect of these two components.

peripheral circulation; local control of blood flow; skin circulation; reflex cooling

While it is clear that local and reflex effector components act, at least in part, through common mechanisms to elicit the SkBF response to environmental cooling, it is also true that the local temperature (T_loc) of the blood vessels and surrounding tissue appear to have significant effects on the reflex reduction of SkBF with cooling (4, 7). Thus the interplay between local sensory and reflex components during general skin cooling is complex and may involve factors that alter the net vasoconstrictor response. Although there are many studies of the mechanisms and effects of direct LC on SkBF (1–7, 9–15, 17–19, 22–23, 28–29, 32) and also multiple studies of the reflex effects of WBC (22–23, 26), little is known regarding how these separate stimuli act together during body cooling; yet it is most often the case that both local and reflex cooling mechanisms are simultaneously operative, for example during environmental or general cold exposure.

Accordingly, we sought to determine the relative roles of the local and reflex components of body cooling on the reduction in SkBF (protocols 1 and 2). We tested whether combined LC (at the site of measurement of SkBF) and WBC (remote from the site of measurement) would have an additive effect on the reduction in cutaneous vascular conductance (CVC) compared with that of the local and reflex components individually. That is, the response to the combined stimulus would equal the sum of the responses to the individual stimuli. The results from those protocols led us to test whether the local thermal environment influences the reflex reduction in SkBF with WBC (protocol 3). To test this possibility, the reflex response in CVC to WBC was observed with and without LC. We hypothesized that LC would result in an attenuation of the reflex response.

	METHODS AND PROCEDURES

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The local Institutional Review Board approved all studies, and volunteer participants were fully informed of the methods and risks before giving written consent. A total of 16 subjects participated (7 women, 9 men; 22–47 yr). All were healthy, nonobese (body mass index 24.4 ± 1.1 kg/m²), nonsmokers, taking no medications, and all refrained from caffeine consumption for at least 12 h before study sessions. Female participants taking oral contraceptives participated in these studies without stratification relative to menstrual phase because it was previously reported that the vasoconstrictor response to local cooling was not affected by reproductive hormone status (2).

The following methods were used in all protocols of the study. SkBF was monitored from the ventral forearm by laser-Doppler flowmetry (model MBF3D, MoorLab) and expressed as laser-Doppler flow (LDF). This technique has been shown to be specific to SkBF and is not influenced by blood flow to underlying skeletal muscle (20, 25). Control of surface temperature at the site of blood flow measurement was accomplished with metal Peltier cooler-heater probe holders. These devices each covered 7 cm² of forearm skin, except for a small (0.28 cm²) aperture in the center. T_loc could be controlled precisely (±0.1°C) and changed rapidly with this device (2, 17, 22, 23, 32). The level and feedback for the control of T_loc were obtained through a copper-constantan thermocouple placed between the probe holder and the skin, with the thermocouple junction placed 0.8 cm from the site of blood flow measurement. Body temperature control was achieved via a water-perfused suit that covered the entire body surface, excluding the head, feet, hands, and areas of blood flow measurement. The weighted electrical average from six thermocouples placed on the calf, thigh, lower back, upper back, abdomen, and chest served as the measure of mean skin temperature (_skin) (27). Blood pressure was measured by the Penaz method from the middle finger (Finapres, Ohmeda, Madison, WI) (8, 21). Mean arterial pressure was continuously obtained from the electrical integration of the blood pressure signal. Heart rate was measured from the pulsatile blood pressure signal. CVC was calculated as the quotient of the blood flow (LDF) and mean blood pressure values. These variables were each sampled once per second by a laboratory computer and stored as 20-s averages (Labview, National Instruments). Study sessions were performed with the subject at quiet rest in the supine position.

Protocol 1: relative local and reflex contributions to SkBF response with skin cooling.   To examine the relative roles of local and reflex cooling on the SkBF response to equal LC and WBC, such as that occurs with environmental cold exposure, participants underwent LC alone and WBC alone and with LC (Fig. 1A). Five subjects (2 women, 3 men) participated in this portion of the study. Participants reported to the laboratory and were instrumented as described above. Each subject was fitted with three combination cooler-heater probe holders. T_loc and _skin were initially held constant at 34°C. Three 15-min cooling conditions were performed: LC alone (site 1; 34–31°C), WBC alone (site 2; 34–31°C), and combination LC and WBC (site 3; both 34–31°C). The pattern of cooling was in a steady ramp. The rate of cooling in all cases was –0.2°C/min and was matched when LC and WBC were performed simultaneously.

View larger version (28K): [in this window] [in a new window]   Fig. 1. A: pattern of control of mean skin temperature (skin) and local temperature (Tloc) at each of the sites of blood flow [laser-Doppler flow (LDF)] measurement in protocols 1 and 2. skin and Tloc at the sites of measurement were held constant at 34°C for the baseline period of 10–15 min. Site 1 then underwent local cooling (LC) for 15 min (31°C protocol 1; 28°C protocol 2), with sites 2 and 3 maintained at 34°C. Whole body cooling (WBC; 34 to 31°C) was conducted in a ramp pattern for 15 min with (site 3) or without (site 2) simultaneous LC (31°C protocol 1, 28°C protocol 2). Temp, temperature. B: protocol 3: influence of LC on the cutaneous vascular conductance (CVC) response to WBC. After baseline, site 1 underwent 15 min LC to 28°C, while site 2 was held at 34°C. Then, 15-min WBC (34–31°C) was conducted. In 3 of the 5 subjects in protocol 3, after a recovery period, a second LC was performed at site 1 for 15–20 min to assess the responsiveness of the locally cooled site to WBC (dashed offset). NT, normothermic local temperature (34°C).

Protocol 3: T_loc influence on reflex response to skin cooling.   The results from protocols 1 and 2 indicate the response in CVC to combined LC and WBC to be similar to that with WBC alone. In the case of protocol 1, there was no significant difference between combined cooling and WBC. Although this might be taken to suggest the reflex component to have the dominant role, such a conclusion has the implicit assumption that the reflex responsiveness is independent of the T_loc. However, previous studies suggest that the temperature of the local tissue is an important factor influencing reflex cutaneous vasoconstrictor mechanisms (4–7, 11, 14, 18, 22–23, 31). Thus, to find the relative roles of LC and WBC in cutaneous vasoconstriction during combined cooling, it was necessary to find the influence of the local thermal environment on the reflex response to WBC. To do this, the responses in CVC to WBC were observed at a LC site and at a normothermic (NT) site. While the NT site was held at 34°C, the LC site was cooled over a 15-min period to 28°C and held constant until CVC was stable. Then 15-min WBC (34 to 31°C) was performed as in protocols 1 and 2 (Fig. 1B). This portion of the study included five subjects (1 women, 4 men). In three of those subjects, the LC site was subjected to further cooling (to 21°C) before restoring temperatures to NT levels (Fig. 1B, area indicated by dashed line) to test whether the initial LC to 28°C had maximally vasoconstricted the skin.

Data analysis.   CVC was expressed relative to initial baseline values for each site as the average over 3 min just before the cooling stimulus. Average final minute values were used to determine maximal CVC responses to cooling conditions. The change in CVC from baseline was expressed as CVC. Maximal CVC responses among cooling conditions were compared by ANOVA with a Student's-Newman-Keuls post hoc test when a significant difference was identified (protocols 1 and 2). Independent sample analysis was used for comparison of LC and NT conditions (protocol 3). Paired sample statistics (Student's paired-t test) were used to assess CVC before and after WBC (protocol 3). Reflex sensitivity was calculated as CVC/change in _skin. This was done for both levels of T_loc in protocol 3. Those sensitivities were then applied to the results from protocol 2, in which the same beginning and ending levels of T_loc and whole body skin temperature were reached. Statistical significance was accepted when P 0.05. All data are presented as means ± SE.

	RESULTS

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Protocol 1.   Figure 2A shows the average responses in CVC to independent and combined equal LC and WBC. LC was performed at one site during neutral body temperature (34°C). WBC alone and combined LC and WBC were then conducted at separate measurement sites. Maximum CVC for the three cooling conditions and the sum of the responses to LC and WBC are presented in Fig. 2B. Maximum responses with WBC alone and with combined LC and WBC were similar (48.4 ± 5 vs. 51.3 ± 8% CVC; P > 0.05). The responses at these two sites were greater than that at the LC only site (29.5 ± 4% CVC; P < 0.05 vs. WBC and combination LC and WBC). The sum of the responses to independent LC and WBC was greater than the response at the combination site (74.9 ± 4.0 vs. 51.3 ± 8.0% CVC, respectively; P < 0.05). Mean arterial pressure rose significantly with WBC (83.7 ± 1.6 baseline to 100.2 ± 2.5 mmHg WBC; P 0.05) but did not change significantly with LC (80.7 ± 2.3 mmHg; P 0.05 relative to baseline).

View larger version (19K): [in this window] [in a new window]   Fig. 2. Results from protocol 1. A: responses in CVC to LC alone, WBC alone, and equal and simultaneous LC and WBC. CVC is presented as 1-min averages and expressed as a percentage of baseline ± SE; n = 5 subjects. All cooling conditions produced a consistent reduction in CVC. B: maximal CVC response [change in CVC from baseline (CVC) ± SE, at 15 min] in the 3 cooling conditions and the arithmetic sum of the independent responses to LC and WBC. Sum LC&WBC, combined local and whole body cooling. Maximum responses with WBC alone and with combined WBC and LC were similar. The response at these 2 sites was greater than at the LC site. The sum of the responses to LC and WBC was greater than that observed with combination cooling. *P < 0.05 vs. local cooling. ^ P < 0.05 vs. other conditions.

View larger version (20K): [in this window] [in a new window]   Fig. 3. Results from protocol 2. A: equipotent local cooling and whole body cooling with skin cooling. Values are CVC ± SE from protocol 2 for LC alone, WBC alone, and combined LC and WBC averaged over 1-min intervals and are expressed as a percentage of baseline; n = 8 subjects. All cooling conditions resulted in a consistent reduction in CVC. B: maximum CVC ± SE for the 3 cooling conditions and the sum of the individual responses to equipotent LC and WBC. The maximum responses for independent LC and WBC were similar and were less than the response at the combination site. However, the sum of the responses to LC and WBC was greater than the response at the combination site. *P < 0.05 vs. local cooling. ^ P < 0.05 vs. other conditions.

View larger version (34K): [in this window] [in a new window]   Fig. 4. Results from protocol 3. A: influence of LC on the response to WBC. Values are CVC ± SE; n = 5 subjects. LC, beginning at time 0, resulted in a gradual reduction in CVC. After CVC stabilization, WBC was conducted (27–47 min). B: left, WBC resulted in significant reductions in CVC at both sites. However, the reduction relative to the original baseline was greater at the NT site. B: right, these differences were no longer present when the data are expressed relative to the baseline immediately before WBC. pre/post WBC, before and at the end of whole body cooling, respectively. *P < 0.05 vs. pre NT. P < 0.05 vs. pre local cooling. P < 0.05 vs. pre NT.

	DISCUSSION

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In the case of protocol 1 (3°C reductions in _skin and T_loc), we make the simplifying assumption that the smaller reduction in T_loc would also have a proportionally smaller influence on the reflex sensitivity to whole body cooling. Thus we estimate the reduction in the sensitivity to whole body cooling as 29% at a T_loc of 31°C, compared with the observed 58% reduction at a T_loc of 28°C. Applying these estimates to the results from protocol 1 yields an estimate of the response to combined cooling to have 66% associated with the reflex reduction from WBC, the remainder being due to the direct and interactive effects of LC. Hence, the fact that the combination cooling in protocol 1 gave a response not statistically distinguishable from that of WBC alone does not mean that the entire response to the combined cooling is attributable to the reflex portion of the response. As developed above, the sensitivity to WBC is lower in the combined response because the final T_loc is lower than that in place with WBC alone, and the sensitivity to WBC is reduced accordingly.

Our results from protocol 1 suggest that local and reflex components do not contribute equally to the reduction in CVC with equal local and whole body degrees of cooling. Independently, they provide different responses with the reflex being the greater (Fig. 2). When the cooling stimuli are combined, our analysis indicates that the reflex is the greater contributor. When equipotent local and reflex cooling stimuli were combined (protocol 2), we observed a reduced role for the reflex and an enhanced role for T_loc. Thus, although the reflex effects have the greater role at the milder levels of local cooling, this would appear to be largely due to the relatively mild independent effect of local cooling and smaller influence on reflex responsiveness at those levels of cooling. When LC is somewhat more marked, but still within normal physiological limits, that component becomes the major contributor to the overall vasoconstrictor response.

How does LC inhibit the reflex response? LC of the blood vessels and surrounding tissue appears to promote some aspects of vasoconstriction and diminish others, primarily by altering synthesis, release, and/or responses to norepinephrine (NE) (1, 3–7, 11–15, 18–19, 22–23, 28–30). LC enhances the response of postsynaptic ₂-adrenergic receptors to NE through mobilization of _2c-receptors to the cell membrane (1, 3, 5–6, 11, 15). However, it also reduces NE synthesis and release from sympathetic nerves (13, 14, 18, 29). Furthermore, LC can influence the vasomotor state of the skin through an alteration of nitric oxide synthase function (32), as well as a number of other nonadrenergic mechanisms (9–10, 26). Taken collectively, the results from these studies provide potential loci where the local thermal environment may have an important influence over the interaction between local and reflex components during general skin cooling.

In terms of the site of interaction between LC and reflex responsiveness, there are other possibilities. One is that the reduction in CVC from LC may have maximally vasoconstricted the skin, removing the capacity for further vasoconstriction in response to reflex increases in sympathetic vasoconstrictor activity. Thompson et al. (28) assessed the adrenergic responsiveness in the cutaneous vasculature in the presence of LC to 24°C. The authors supplied exogenous NE during direct cooling and found that skin of younger, but not older, subjects retains the capacity to respond to NE by further vasoconstriction beyond that achieved by LC alone (28). Thus it appears that the lower reflex sensitivity in the present study was not because skin was maximally vasoconstricted by LC. Although the age of participants (22–47 yr) in the present investigation is greater than in their younger group, it is less than the range defined for their older group and in others, addressing the effect of age on adrenergic responses (28, 31). The conclusion that locally cooled skin retains the capacity for further vasoconstriction is also supported by our observation in a limited number of subjects that additional LC could stimulate further vasoconstriction.

Although the skin was not maximally vasoconstricted by LC, the change in baseline may nevertheless play an important role in the associated effects of LC on reflex responsiveness. This possibility is strongly suggested by the similar percentage reflex reductions in CVC in response to WBC, with and without LC in protocol 3. It may be that, at these levels of LC, the effect of the lowered baseline is more important than the effects on adrenergic vasoconstrictor mechanisms. It is important to recognize that, for the purposes of the present study, changes in CVC from the initial baseline (before any cooling) were analyzed because it is those changes we aimed to explain relative to the local and reflex components. The interaction probably involves both baseline effects and alterations in adrenergic mechanisms. The level of cooling, both local and whole body, employed in this study is well within the physiological spectrum. However, more severe levels of cooling are not outside normal environmental exposure and may produce different findings from the present study.

The potential for an "order effect" is yet another possible site of interaction in need of consideration. The design of protocol 3 did not allow us to directly address this issue, as WBC was performed only after LC had been maintained. However, had WBC been maintained and LC done on top of that, we might expect a reduced response to LC.

In summary, the results from these studies suggest that, at equal levels of LC and WBC (i.e., environmental cooling), the reflex component has the larger role. With equipotent combined cooling, local effects dominate. In either case, LC consistently causes a reduced reflex responsiveness. Thus the reduction in CVC with general cold exposure is in part due to the local effects of direct skin cooling and in part due to the reflex effects of remote skin cooling. The reflex effects are a relatively straightforward engagement of sympathetic vasoconstrictor activity (16, 22, 26). The mechanism through which LC has its effects is more complex in that it causes vasoconstriction in part through local stimulation of vasoconstrictor nerves, in part though nonadrenergic mechanisms, and in part through inhibition of the effects of reflex vasoconstriction (1, 3, 4, 7, 11, 12, 14, 17, 19, 23, 28, 32). This latter effect, including reductions in baseline levels of CVC, is the major means by which these two components interact and is why the combined effect is less than that predicted by a simple additive model.

	GRANTS

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This study was supported by National Heart, Lung, and Blood Institute (NHLBI) Grant HL-059166. G. E. Alvarez was supported by NHBLI Grant T32 HL-04776.

	ACKNOWLEDGMENTS

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The authors gratefully acknowledge the efforts of the research participants in this investigation.

Present address of G. E. Alvarez: c/o Guidant Corporation, 4100 Hamline Ave. N., St. Paul, MN 55112.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. M. Johnson, Dept. of Physiology-MSC 7756, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900 (e-mail: johnson{at}uthscsa.edu)

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.

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This Article Abstract Full Text (PDF) Free All Versions of this Article: 100/6/2083    most recent 01265.2005v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Alvarez, G. E. Articles by Johnson, J. M. Search for Related Content PubMed PubMed Citation Articles by Alvarez, G. E. Articles by Johnson, J. M.