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1 Intercollege Graduate Degree Program in Physiology
2 Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, PA 16802-6900, USA
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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CVCbase). At one site, five doses of NA (10–10–10–2
M) were sequentially infused via intradermal microdialysis during cooling while the other 24°C site served as control (Ringer solution + cooling). At control sites, VC due to cooling alone was similar in young versus older (–54 ± 5 versus
–56 ± 3%
CVCbase, P
= 0.46). In young, NA infusions induced additional dose-dependent VC (10–8, 10–6, 10–4 and 10–2
M: –70 ± 2, –72 ± 3, –78 ± 3 and –79 ± 4%
CVCbase; P < 0.05 versus control). In older subjects, further VC did not occur until the highest infused dose of NA (10–2
M: –70 ± 5%
CVCbase; P < 0.05 versus control). When cutaneous arterioles are sensitized to NA by direct cooling, young skin exhibits the capacity to further constrict to NA in a dose-dependent manner. However, older skin does not display enhanced VC capacity until treated with saturating doses of NA, possibly due to age-associated decrements in Ca2+ availability or 
2C-adrenoceptor function.
(Received 7 December 2004;
accepted after revision 2 February 2005;
first published online 10 February 2005)
Corresponding author C. S. Thompson: The Pennsylvania State University, 119 Noll Laboratory, University Park, PA 16802, USA. Email: cst116{at}psu.edu
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Introduction |
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Local cooling of cutaneous blood vessels evokes several vascular responses that alter responses to noradrenaline (NA) (Vanhoutte & Shepherd, 1970; Janssens & Vanhoutte, 1978; Flavahan et al. 1985). In vivo, local cooling leads to substantial VC mediated through 2-adrenergic receptors (ARs) (Flavahan et al. 1985; Ekenvall et al. 1988; Cankar et al. 2004). In vitro, local cooling increases intracellular Ca2+ mobilization as well as Ca2+ sensitivity. Additionally, local cooling increases the number of 2-ARs on the vascular smooth muscle cell surface by stimulating the translocation of 2C-ARs from the Golgi apparatus to the cell membrane (Chotani et al. 2000; Jeyaraj et al. 2001; Bailey et al. 2004). These intracellular responses to local cooling enhance the capacity for NA-mediated VC by augmenting the sensitivity of cutaneous vessels to the effects of NA. However, studies that have addressed the changes evoked by local cooling have only used young animal or human thermoregulatory models; very little is known regarding how local cooling affects VC in aged human skin.
The purpose of the present study was to examine the effects of local cooling on aged skin. Specifically, we tested the hypotheses that (1) VC due to local cooling alone is blunted in aged skin, and (2) the heightened sensitivity to NA induced by local cooling observed in young skin is attenuated in aged skin.
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Methods |
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Eleven young (18–30 years; 6 men, 5 women) and 11 older (62–76 years; 5 men, 6 women) subjects participated in the present study. All young women were tested during the early follicular phase of the menstrual cycle and were not taking oral contraceptives; all older women were post-menopausal and were not taking hormone replacement therapy. All subjects underwent a standardized medical screening and were healthy, normotensive, non-obese non-smokers. No subjects were taking any medications that might alter cardiovascular responses to cooling. Subjects abstained from alcohol and caffeine for 12 h prior to coming to the laboratory for the study but were permitted to eat a modest breakfast the morning of the experiment. Approval was obtained from the Institutional Review Board of The Pennsylvania State University. Each subject gave verbal and written informed consent prior to participation in the study, and all procedures conformed to the standards of the Declaration of Helsinki.
Instrumentation
Subjects arrived at the laboratory between 08.00 and 09.00 h on the morning of the experiment. Two microdialysis fibres (MD-2000, Bioanalytical Systems, West Lafayette, IN, USA) were placed into the ventral surface of the right forearm using sterile technique. For each fibre, a 25-gauge needle was inserted into the skin and guided horizontally through the skin such that entry and exit points were approximately 2 cm apart. The fibre, consisting of a 10 mm membrane (320 µm outer diameter, 20 kDa molecular mass cut-off) and connective tubing attached to either end of the membrane, was threaded through the needle. The needle was then withdrawn, leaving the membrane in the skin. After insertion of both fibres, subjects rested quietly for approximately 90 min to allow local hyperaemia due to insertion trauma to subside. At this time, local skin temperature (Tloc) was clamped at 34°C at both microdialysis sites using peltier elements (TecThermo Temperature Controller 1575, Menlo Park, CA, USA).
Skin blood flow was measured using laser Doppler flowmetry (LDF; MoorLAB, Moor Instruments, UK). LDF probes were placed directly over each microdialysis site, and LDF data were collected continuously throughout the experiment. Arterial blood pressure was monitored periodically throughout the experiment via brachial auscultation, and mean arterial pressure (MAP) was calculated as [(1/3 systolic blood pressure) + (2/3 diastolic blood pressure)]. Skin blood flow was converted to cutaneous vascular conductance (CVC), which was calculated as the ratio of LDF flux to MAP, and expressed as raw CVC units, CVC units, and percentage change from baseline CVC values (%
CVCbase).
Protocol
After the microdialysis fibres were in place, lactated Ringer solution was infused through the fibres at a rate of 2 µl min–1 using a microinfusion pump (Harvard 22, South Natick, MA, USA) for approximately 90 min. After hyperaemia subsided and a steady-state thermoneutral baseline (Tloc = 34°C) was established, Tloc at both sites was lowered to 24°C at a rate of 3°C min–1. Once skin blood flow reached a new, cooled steady state (approx. 10 min), NA (10–10 M) was infused for 5 min at one site, while the other site continued to receive only Ringer solution and served as control. Following NA infusion, lactated Ringer solution was infused at the NA site as washout for approximately 20–30 min, and Tloc was then increased to 34°C. Once skin blood flow recovered to initial baseline values, this protocol was repeated for each subsequent dose of NA (10–8, 10–6, 10–4 and 10–2 M).
NA and ascorbic acid (NA preservative; 1 mg ml–1) were obtained from Sigma Chemical (St Louis, MO, USA) and were mixed just prior to usage. All NA dilutions were dissolved in lactated Ringer solution and sterilized using syringe microfilters (Acrodisc, Pall, Ann Arbor, MI, US).
Data collection and analysis
Data were recorded and stored as one-minute averages using computer software (LabView) and a data acquisition system (National Instruments, Austin, TX, USA). At NA sites, VC was defined as the lowest CVC 1-min average observed after the start of NA infusion and prior to rewarming; CVC values at control sites were averaged over that same time period (approximately 7 min). Data were analysed using Student's t test (subject characteristics), three-way analysis of variance (ANOVA) with Tukey-Kramer post hoc tests, and planned comparison tests when significant differences were detected. Statistical significance was set at
= 0.05. Values are expressed as means ±
S.E.M., unless otherwise noted.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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CVCbase, P
= 0.01; 10–6
M: –55 ± 6
versus
–72 ± 3%
CVCbase, P
= 0.004; 10–4
M: –54 ± 5
versus
–78 ± 3%
CVCbase, P < 0.0001; 10–2
M: –53 ± 5
versus
–79 ± 4%
CVCbase, P < 0.0001). Analysis of absolute CVC units supports these results, suggesting that VC due to NA infusion progresses beyond VC due to cooling alone (control versus NA, 10–10
M: 0.15 ± 0.02 versus 0.15 ± 0.02 CVC units, P
= 0.9; 10–8
M: 0.12 ± 0.01 versus 0.10 ± 0.02 CVC units, P
= 0.69; 10–6
M: 0.12 ± 0.01 versus 0.09 ± 0.01 CVC units, P
= 0.24; 10–4
M: 0.12 ± 0.02 versus 0.07 ± 0.01 CVC units, P
= 0.05; 10–2
M: 0.13 ± 0.02 versus 0.06 ± 0.01 CVC units, P
= 0.03).
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CVCbase) comparisons (P > 0.3). At NA sites, the first four doses of NA failed to induce additional VC compared with VC at control sites (control versus NA, 10–10
M:–46 ± 3 versus
–50 ± 5%
CVCbase, P
= 0.41; 10–8
M: –56 ± 4
versus
–58 ± 6%
CVCbase, P
= 0.79; 10–6
M: –61 ± 2
versus
–60 ± 4%
CVCbase, P
= 0.81; 10–4
M: –60 ± 3
versus
–71 ± 6%
CVCbase, P
= 0.06). Additional VC due to NA infusion was only observed at the final and highest dose of NA (control versus NA, 10–2
M: –57 ± 3 versus
–70 ± 5%
CVCbase, P
= 0.03). Again, analysis of raw CVC units supports these findings and extends them to indicate that NA infusion at all doses failed to evoke further VC in aged skin. Specifically, there was no difference in VC between NA and control sites at any dose of NA (control versus NA, 10–10
M: 0.15 ± 0.02 versus 0.19 ± 0.04 CVC units, P
= 0.15; 10–8
M: 0.12 ± 0.02 versus 0.14 ± 0.02 CVC units, P
= 0.47; 10–6
M: 0.11 ± 0.01 versus 0.13 ± 0.02 CVC units, P
= 0.47; 10–4
M: 0.11 ± 0.01 versus 0.08 ± 0.01 CVC units, P
= 0.32; 10–2
M: 0.13 ± 0.02 versus 0.08 ± 0.01 CVC units, P
= 0.07).
In Fig. 2, VC responses to NA during cooling, expressed as a change in absolute CVC values, are compared with each cooled baseline at NA sites just prior to NA infusion (i.e. site-specific control). In young subjects, significant decreases in CVC occurred at all NA doses in a dose-dependent manner compared with pre-NA cooled baselines (10–10
M: –0.045 CVC units, P
= 0.01; 10–8
M: –0.050 CVC units, P
= 0.006; 10–6
M: –0.072 CVC units, P
= 0.0001; 10–4
M: –0.076 CVC units, P < 0.0001; 10–2
M: –0.082 CVC units, P < 0.0001). In contrast, older subjects did not exhibit additional VC due to NA until the final two doses of NA (10–10
M: 0 CVC units, P
= 0.99; 10–8
M: 0.015 CVC units, P
= 0.39; 10–6
M: 0.002 CVC units, P
= 0.91; 10–4
M: –0.043 CVC units, P
= 0.02; 10–2
M: –0.036 CVC units, P
= 0.05). Significant age differences in VC response to NA were detected at three doses (young versus older, 10–8
M: –0.050 versus 0.015 CVC units, P
= 0.005; 10–6
M: –0.072 versus 0.002 CVC units, P
= 0.002; 10–2
M: –0.082 versus
–0.036 CVC units, P
= 0.048), with a fourth dose displaying a clear tendency for an age difference (young versus older, 10–10
M: –0.045 versus 0 CVC units, P
= 0.051).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Local cooling-mediated VC
The majority of thermoregulatory research that has investigated age-related changes in VC responses to cooling has focused on reflex-mediated VC. Reflex-mediated VC is stimulated by whole-body cooling and involves the release of NA and co-transmitters from sympathetic nerve terminals adjacent to cutaneous blood vessels. Ageing impairs reflex-mediated VC, primarily by blunting NA-mediated responses and abolishing co-transmitter-mediated responses (Thompson & Kenney, 2004).
However, reflex-mediated VC bears little mechanistic resemblance to the neurovascular events associated with local cooling. In vitro, local cooling augments the capacity to respond to NA without directly stimulating its release from nerve terminals. Local cooling may increase the available 2-AR population by stimulating translocation of intracellular 2C-ARs to the surface of the smooth muscle cell (Jeyaraj et al. 2001; Bailey et al. 2004). Additionally, local cooling decreases neuronal NA re-uptake and increases intracellular Ca2+ mobilization and Ca2+ sensitivity in vascular smooth muscle cells (Janssens & Vanhoutte, 1978; Vanhoutte, 1980; Chotani et al. 2000; Jeyaraj et al. 2001; Philipp et al. 2002; Chotani et al. 2004). Conversely, NA release from sympathetic nerves is reduced with direct local tissue cooling (Vanhoutte, 1980; Janssens et al. 1981; Flavahan, 1991), so the enhanced VC capacity that results from local cooling occurs despite a depressed release of NA from sympathetic nerves.
Paradoxically, local skin cooling in vivo stimulates cutaneous VC in the absence of exogenously administered or reflexly released NA, as was seen in the present study. Several human in vivo studies indicate that this response is mediated by 2-AR stimulation (Ekenvall et al. 1988; Pergola et al. 1993; Cankar et al. 2004), and Pergola et al. (1993) and Johnson et al. (2004) suggest that the sympathetic release of NA (abolished by bretylium administration in both studies) is necessary to induce this response. Both Pergola et al. (1993) and Johnson et al. (2004) further speculate that this NA-dependent phase of VC may be mediated by a local cooling-induced increase in the release of NA during local cooling, arguing against the in vitro conclusions of Vanhoutte (1980), Janssens et al. (1981) and Flavahan (1991) that suggest that pre-synaptic NA release is depressed with local cooling.
Although these two arguments seem to be mutually exclusive (dependence on sympathetic NA versus reduced NA release), it is possible that they simply articulate two different aspects of the same response to local cooling. The synthesis of the two arguments suggests that it is possible that local cooling-induced VC, such as that observed in the present study, is indeed dependent on a release of NA from sympathetic nerve endings, as Pergola et al. (1993) and Johnson et al. (2004) suggest. However, rather than stimulating NA release, local cooling may still act as a depressant, permitting only tonically released NA to act on an augmented 2-AR population with greater Ca2+ availability.
In the present study, it was not possible to quantify 2-AR membrane cycling or Ca2+ dynamics to determine their contributions to the VC response. However, it is possible that at least one of these mechanisms may have participated in the local cooling VC response observed in the present study. The time course of cooling-induced 2C-AR translocation per se has not yet been firmly established; however, Bailey et al. (2004) noted that 2-AR stimulation in mouse tail arteries at 28°C doubled the intracellular Ca2+ mobilization compared with that observed in arteries at 37°C after 3 min, suggesting a relatively short time course for cooling-induced changes in Ca2+ dynamics. Considering the 2-AR-dependent nature of local cooling-induced VC in vivo, it is possible that similar alterations in Ca2+ activity may have contributed to the responses observed in the present study. Further research is necessary to clarify the time course of these in vitro mechanisms and their role(s) in human cutaneous in vivo VC responses.
Interestingly, after longer periods of local cooling (20–30 min), a second, non-adrenergic mechanism of VC may also contribute to the overall cutaneous VC response in vivo in humans (Pergola et al. 1993; Johnson et al. 2004). However, it is unlikely that this additional VC mechanism contributed to the responses observed in the present study, because the duration of local cooling was in all likelihood not long enough to engage this second, non-adrenergic mechanism.
Although there is presently little data addressing the effects of advancing age on the mechanisms of local cooling, we originally hypothesized that older subjects would exhibit blunted VC in response to local cooling compared with young subjects. Healthy ageing is generally associated with impaired cutaneous vasomotor function, including blunted reflex VC and vasodilatation as well as attenuated vasodilatation in response to local heating (Kenney & Armstrong, 1996; Kenney et al. 1997; Minson et al. 2002; Pierzga et al. 2003; Thompson & Kenney, 2004). However, the findings from the present study indicate that VC in response to local cooling alone is unchanged with age, suggesting that in older human skin, the ability to constrict cutaneous blood vessels in response to direct local cooling to 24°C is preserved.
Local cooling + NA infusion
Localized cooling of the skin rarely occurs in isolation but rather more typically occurs in conjunction with whole-body cooling, which stimulates the reflex release of NA from nerve terminals. This, in turn, enables cutaneous vessels to respond to both increased NA release (reflex mechanisms) and increased sensitivity to NA (local mechanisms) cooperatively to maximize VC in the cold, thereby minimizing heat loss. Experimentally, NA administration during local cooling approximates the co-activation of these two pathways in a controlled manner, more fully characterizing the effects of age on cutaneous VC.
In young subjects, graded NA administration during local skin cooling to 24°C evoked dose-dependent VC beyond the extant VC due to cooling alone. This additive response was observed when VC at NA sites was compared with cooling-induced VC at a separate control site (see Fig. 1A) and when VC at NA sites was compared with cooling-induced VC at the same site just prior to NA infusion (see Fig. 2), obviating the possibility that the observed differences between cooling + NA-mediated VC and cooling-induced VC were simply due to site differences. It is possible that the additional VC observed during concurrent cooling and NA administration may have been mediated by increased intracellular Ca2+ mobilization and Ca2+ sensitivity in vascular smooth muscle cells and/or increased 2C-AR expression on the surface of the smooth muscle cells. Chotani et al. (2004) suggest that although 2A-AR expression predominates when cutaneous vessels in vitro are not stressed, the up-regulated 2C-AR expression which is associated with cold exceeds 2A-AR expression by as much as 4 times. When these conclusions are applied to in vivo responses observed in the present study, it is possible local cooling may enable the formation of a substantial 2C-AR reserve capable of binding high concentrations of NA and initiating and maintaining augmented VC. Again, further research is necessary to clarify the role(s) of these mechanisms in human cutaneous in vivo VC responses.
In older subjects, graded NA administration during local skin cooling did not evoke any additional VC until saturating doses of NA were infused. As in the young subject group, VC at NA sites was compared with cooling-only data obtained at both a separate control site and at the cooled NA site just prior to NA infusion. The comparison using the NA site as its own control indicated that significant VC occurred at the last two doses (see Fig. 2), whereas the comparison with the separate control site indicated significant VC only at the last dose (see Fig. 1B). However, the differences between these two sets of data are negligible, and together they suggest that older cutaneous vessels cannot accommodate further VC unless treated with saturating doses of NA.
Due to the nature of this study, it was not possible to precisely identify the mechanism(s) responsible for the observed age differences in VC during concurrent local cooling and graded NA administration. However, it is likely that one or more post-junctional events stimulated by local cooling are altered with age. First, it is possible that Ca2+ utilization during local cooling changes with human ageing. During local cooling, extracellular Ca2+ flux into vascular smooth muscle cells is depressed (Janssens & Vanhoutte, 1978; Vanhoutte, 1980; Rusch et al. 1981; Flavahan et al. 1985; Gomez et al. 1991) while intracellular Ca2+ mobilization and sensitivity is up-regulated (Bailey et al. 2004). However, ageing is conversely associated with a greater dependence on extracellular Ca2+ influx and a corresponding impairment of intracellular Ca2+ movement (Marin & Rodriguez-Martinez, 1999; Rubio et al. 2002). If Ca2+ influx and mobilization during local cooling is sufficiently impaired in older humans, it is possible that VC due to cooling alone may maximally utilize available Ca2+, with little additional capacity to accommodate further VC in response to simultaneous cooling and NA infusion.
An alternative explanation for blunted aged VC in response to NA administration during cooling may involve impairment of -AR function. AR desensitization occurs in many vascular beds with ageing, including skin (Nielsen et al. 1992; Hogikyan & Supiano, 1994; Vila et al. 1997; Frank et al. 2000). Studies that have investigated AR subtype desensitization report blunted 1-AR responsiveness to NA, while results regarding 2-AR function are equivocal, indicating either maintained or impaired responsiveness with ageing (Supiano et al. 1991; Nielsen et al. 1992; Folkow & Svanborg, 1993; Vila et al. 1997; Marin & Rodriguez-Martinez, 1999; Dinenno et al. 2002). However, these studies have only been performed in thermoneutral settings, i.e. under conditions where only 2A-ARs are expressed on the surface of the vascular smooth muscle cells (there is no evidence supporting 2B-AR expression on cutaneous arterioles), while 2C-ARs are ‘silent’ and not present on the cell membrane. It is therefore also possible that unique changes in 2C-AR expression or function may occur with age, especially considering their unique physiological role in the control of cutaneous blood flow. If 1-, 2A- and/or 2C-AR sensitivity is impaired with age, then the -AR function may only be sufficient to support VC evoked by cooling alone, with little reserve capacity left to accommodate additional VC due to NA infusion. Further research is necessary to firmly conclude whether/which cutaneous 2-AR subtypes are affected by ageing, under both thermoneutral and cooled conditions.
Limitations
The present study did not fully address all mechanisms in effect during local cooling. Although NA infusion was deemed an appropriate model to examine the effects of local cooling on AR-mediated VC, NA infusion alone does not provide full insight into the effects of local cooling on sympathetic reflex VC. Reflex VC is mediated by both NA and sympathetic co-transmitters, possibly neuropeptide Y (NPY) or adenosine triphosphate (ATP) (Stephens et al. 2001, 2002, 2004; Thompson & Kenney, 2004), raising the possibility that local cooling may also modulate co-transmitter-mediated VC. In vitro studies examining the effects of cooling on isolated cutaneous vessels have concluded that both NPY- and ATP-mediated VC or potentiation of VC is augmented by local cooling (Vanhoutte, 1980; Padilla et al. 1997; Garcia-Villalon et al. 2000). Additionally, reflex co-transmitter-mediated VC is functionally abolished in aged human skin, suggesting a differential effect of local cooling on reflex VC with advancing age.
Summary
This study presents evidence that while the cutaneous VC response to local cooling to 24°C is preserved in older humans up to age 76, cutaneous VC in response to graded NA administration concurrent with local cooling is impaired in aged skin. This attenuated response may be due to impaired Ca2+ availability or 2C-AR desensitization to NA, as is seen in other AR subtypes with human ageing. Conclusions from the present study help to characterize the age-associated changes surrounding the mechanisms of local skin cooling. These findings may also further clarify age-related impairments in overall VC capacity that predispose older humans to excessive heat loss and subsequent hypothermia.
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P < 0.05 versus young.