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Department of Physiology, The University of Texas Health Science Center, San Antonio, Texas
Submitted 20 August 2004 ; accepted in final form 29 November 2004
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ABSTRACT |
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 TOP ABSTRACT METHODS AND PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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human; peripheral circulation; local control of blood flow; skin circulation; microdialysis; iontophoresis; neuropeptide Y; norepinephrine; axon reflex
Local thermal control of skin blood flow has also been the subject of considerable attention. Direct local warming of the skin leads to a vasodilation that involves nitric oxide and sensory nerves (20, 25, 38). With respect to direct local cooling, several lines of evidence point to an involvement of the sympathetic vasoconstrictor system in the reduction of skin blood flow. Postsynaptic 
2-adrenergic receptors have an enhanced affinity for norepinephrine, perhaps mediated through translocation of 2C-receptors to the membrane through a Rho kinase mechanism, and there is an increased 1-receptor reserve, these effects countering negative effects of cooling on norepinephrine synthesis and release and on contractile function (2, 4, 6, 29, 41). Previous studies in our laboratory show that presynaptic blockade of sympathetic vasoconstrictor nerves with bretylium, applied to the intact skin iontophoretically, reverses the initial vasoconstrictor response to local cooling to one of vasodilation (31) and reverses the inhibition by local cooling of reflex cutaneous vasodilation (30). The implication is that local skin cooling may enhance or stimulate transmitter release from sympathetic vasoconstrictor nerve endings in the skin. However, this conclusion relies on the specificity to sympathetic nerves of the blockade and does not indicate the relative roles of norepinephrine and any coreleased transmitters (26–27, 36–37, 39–40). Also, the studies to date do not indicate whether the effects of direct cooling act through sensory elements in the skin, as appears to be the case with local heating (25, 38) or if the vasoconstriction is through a more direct effect of cooling on vascular smooth muscle and/or sympathetic nerve endings.
We tested further the hypothesis of sympathetic involvement in the cutaneous vascular response to local cooling through local blockade of adrenergic receptors. We also examined whether blockade of receptors for neuropeptide Y (NPY) might indicate a role for that known sympathetic cotransmitter (39). Finally, we sought to discover whether there was a role for sensory elements in the skin by applying local anesthetic to the areas of cooling and blood flow measurement.
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METHODS AND PROCEDURES |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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- and 
-receptors, 3) local blockade of NPY receptors, and 4) topical application of anesthetic cream. Methods of measurement and the local cooling protocols, described below, were the same in all cases. Skin blood flow was monitored from the ventral forearm by laser-Doppler flowmetry (Moor MBF3D) (17, 28). Control of surface temperature at the site of blood flow measurement was accomplished with metal Peltier cooler/heater probe holders, which covered 7 cm2 of forearm skin except for a small (0.28 cm2) aperture in the center. Local skin temperature could be controlled precisely (±0.1°C) and could be changed rapidly with this device. The level and feedback for the control of local skin temperature 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. Blood pressure was measured by the Penaz method from a finger (Finapres, Ohmeda) (29). 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. Cutaneous vascular conductance (CVC) was calculated from the flow and blood pressure values. These variables were each sampled once per second by a laboratory computer and stored as 20-s averages.
Part 1: blockade of transmitter release from sympathetic vasoconstrictor nerve terminals.
To find whether presynaptic inhibition of vasoconstrictor nerve function had an effect on cutaneous vascular responses to local cooling, we applied bretylium tosylate (23) to a 0.6-cm2 area of skin by iontophoresis to each of eight subjects (3 women and 5 men). This application was made according to earlier studies in the laboratory (19, 30, 31) and involved passing 400 µA/cm2 for 10 min into ventral forearm skin. One hour later, the subject rested supine and had one laser-Doppler flow probe and holder placed over the site of bretylium application and a second probe/holder combination placed over a nearby, untreated site. Initial local temperatures were held at 34°C. As shown for one subject in Fig. 1, after a 10-min baseline period, local cooling of those sites commenced by lowering the temperature to 29°C over 
5 min. That temperature was then held for an additional 30 min. This rate and intensity of cooling were standardized across all protocols and were not perceived as painful or uncomfortable. This protocol is similar to portions of an earlier study (31) and was repeated here to establish the response to local cooling with this protocol design.
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- and -adrenergic effects of norepinephrine was important in the cutaneous vascular response to local cooling, in five subjects (1 woman and 4 men) we applied a combination of yohimbine and propranolol to antagonize those receptors. The antagonists were applied continuously by microdialysis in a solution of yohimbine (5 mM) and propranolol (1 mM). We have previously found that this combination and level of adrenergic antagonists was effective in inhibiting the cutaneous vascular responses to exogenous norepinephrine (36–37, 39). Subjects had two microdialysis probes placed intradermally (3, 7, 20, 39). These probes, described previously (3, 7, 20), consisted of 1 cm of microdialysis tubing (inner diameter 200 µm, 18 kDa nominal molecular weight cutoff) attached at each end to polyimide tubing. Before implantation, the area of ventral forearm skin was rendered temporarily anesthetic by the 5- to 8-min application of an ice pack. A 25-gauge needle was introduced aseptically for 3.3 cm into the skin before exiting. The microdialysis probe and connecting tubing were introduced into the skin via the needle, and the needle was removed, leaving the probe in place. Both probes were placed in this manner and at least 2 h were allowed for the effects of the local cold and of the probe placement to subside (1). The exchange areas for the different probes were 3–5 cm apart. The subject was ambulatory during this period. The protocol began with the microdialysis probes perfused with sterile Ringer solution for 20 min at 4 µl/min. The perfusate for one probe was then changed to the yohimbine-propranolol combination, in Ringer solution, with Ringer solution continuing at the other site. After 40 min, local cooling commenced at both sites, in which the temperature at those sites was reduced from 34 to 29°C over 5 min and the lower temperature was maintained for 30 min (see Fig. 1). Finally, norepinephrine (10 mM) was perfused through the microdialysis tubing to the sites to test for the adequacy of blockade (39). A reduction in CVC at a yohimbine-propranolol-treated site of >10% was taken to indicate inadequate blockade, and data from any such site were excluded from further analysis. Part 3: postsynaptic blockade of Y1 receptors for NPY. This portion was conducted to discover whether the cutaneous vascular responses to local cooling were affected by blockade of Y1 receptors for the sympathetic cotransmitter NPY. Procedures were the same as for part 1. The exception was that a 10 µM solution of the NPY Y1 antagonist BIBP-3226 (8, 13, 34, 39), in Ringer solution, was perfused at 4 µl/min through one of two microdialysis membranes. Sterile Ringer solution was perfused through the other. The timing and local temperature protocol were the same as for part 2. This part included 3 women and 2 men.
Part 4: sensory blockade. To test for a role for sensory nerves in the cutaneous vascular response to local cooling, in eight subjects (3 women and 5 men), anesthetic cream consisting of lidocaine (2.5%) and prilocaine (2.5%) (Emla, Astra) was applied to the 7-cm2 area subjected to local temperature control. Emla was applied for 3–4 h under occlusive dressing. The area was tested for sensory loss at the beginning of the study and again after responses to local cooling had been assessed. Failure to achieve anesthesia in either case caused the data not to be included. To test whether the local anesthetic blocked sympathetic nerves, the cutaneous vasoconstrictor response to whole body cooling was assessed. Subjects dressed in water-perfused suits (19, 36) that covered the body surface except for the head, hands, feet, and areas of blood flow measurement. Cold water was pumped through the suit tubing to reduce whole body skin temperature from 34 to 31°C over 3 min. After subjects were rewarmed, a recovery period of at least 10 min was allowed before the local cooling protocol was continued. The protocol for part 4 was otherwise the same as for parts 1–3 in which areas subjected to treatment and nearby untreated areas were locally cooled from 34 to 29°C over 5 min and held at the cooler temperature for 30 min.
Data analysis. Our earlier observations with the effects of presynaptic adrenergic blockade with bretylium on the responses to direct local cooling noted an initial vasodilation in treated areas followed by a net vasoconstriction after 30 min (31). Consequently, data for CVC from parts 1–4 were analyzed for the first 5 min of local cooling and for the final 5 min. Those data for CVC were taken as the average over 1 min around the peak of the response from the selected period. CVC was expressed relative to the baseline values for each site obtained as the average over the 5 min just before the local cooling. Absolute values for CVC (laser-Doppler flowmeter output divided by arterial pressure) were used to ascertain whether sites were at unusually high or low values before local cooling as a result of the pharmacological background or the preparatory procedures. Data from such sites were not included in any further analysis. Analysis was by paired statistics or, when appropriate, repeated-measures ANOVA. Statistical significance was accepted when P < 0.05.
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RESULTS |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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- and -adrenergic receptors (36–37, 39). A response like that seen at control sites would implicate some mechanism independent of norepinephrine and those receptors, whereas a response like that seen after bretylium pretreatment would suggest participation by norepinephrine in at least the initial vasoconstriction. Although baseline values tended to be higher at the yohimbine-propranolol-treated sites (2.46 ± 0.98 U/mmHg) than at control sites (1.28 ± 0.52 U/mmHg), this did not achieve statistical significance (P = 0.098). Figure 3 shows results averaged from five subjects from sites continuously treated with yohimbine and propranolol by microdialysis and from sites at which Ringer solution was administered by microdialysis. At the latter sites, CVC was significantly reduced both early (P < 0.05) and later in the 30 min of local cooling. At yohimbine-propranolol-treated sites, CVC rose significantly (P < 0.05) early but showed a net vasoconstriction by the end of local cooling (P < 0.05). These findings suggest a role for norepinephrine, acting through adrenergic receptors, in the initial vasoconstrictor response to local cooling at untreated sites.
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DISCUSSION |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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In the present study, we confirmed the above observation. This confirmation was both through repeating the observations with bretylium and by blockade of - and -adrenergic receptors. Inasmuch as these approaches interrupted the vasoconstrictor system at different sites, the above conclusion that the sympathetic vasoconstrictor system is required for the vasoconstrictor response early in local cooling is considerably strengthened.
Our method of inhibiting the adrenergic receptors involved infusion of yohimbine and propranolol by microdialysis. This followed from earlier studies in our laboratory designed to study the transmitter involvement in the reflex vasoconstrictor responses to general skin cooling (not including cooling of the area of blood flow measurement) (36–37, 39). In those studies, we found that blockade of adrenergic receptors removed most but not all of the reflex vasoconstrictor response to cold stress. We also found that these levels of yohimbine and propranolol effectively eliminated vasomotor responses to norepinephrine. This indicates that -receptors and, importantly, both major subtypes of -receptors were blocked, which is in keeping with studies showing yohimbine to have nonspecific -receptor antagonism at these levels (12). It was also important that -receptors be blocked to remove completely the effects of norepinephrine (36–37). Thus we are confident that the effects of local cooling at sites treated with yohimbine and propranolol in the present study were due to mechanisms that are independent of norepinephrine.
In those earlier studies, we found that yohimbine and propranolol block more completely the effects of norepinephrine than the reflex effects of whole body cooling, leading to the conclusion that a cotransmitter was involved and accounted for perhaps 30% of this reflex response (36–37, 39). We also found that treatment with an NPY antagonist, when given alone, reduced the reflex vasoconstrictor response to whole body cooling and, when given in combination with yohimbine and propranolol, essentially eliminated the reflex response (39). In the present series, blockade of NPY Y1 receptors with the same methodology had no apparent effect on the response pattern to local cooling. Thus any role for NPY in the response to local cooling is subtle compared with a more tangible role with respect to the reflex responses to whole body cooling. This finding suggests that the release of transmitter from sympathetic terminals as provoked by local cooling differs from that associated with centrally evoked action potentials. It may be that the pattern of membrane depolarization necessary for release of the vesicles containing NPY is achieved via nerve activity but not by local cooling. However, this speculation requires further examination.
The release of transmitter from sympathetic nerves for the initial vasoconstriction with local cooling is engaged by sensory nerves, as demonstrated by the effects of topical anesthetic. The pattern of the response to local cooling in this case was quite similar to that seen after pre- or postsynaptic interruption of sympathetic neural functions: the initial vasoconstriction in treated skin was reversed to a significant vasodilation, whereas the longer-term vasoconstriction was sustained. Thus the initial vasoconstriction with local cooling requires both intact sympathetic function and intact sensory function. Importantly, these effects of topical anesthetic were not due to local anesthetic blockade of sympathetic fibers and thereby cannot be explained as redundant to the effects of bretylium or adrenoceptor antagonism. Whole body cooling evoked a significant vasoconstriction at best only slightly (and nonsignificantly) reduced from that at control sites. At the same time, tests of sensory function found the sites to be completely anesthetic. Thus there is a requirement that local sensory function be intact for the sites to be responsive to the initial effects of local cooling.
The requirement for intact sensory function for the initial vasoconstrictor response to local cooling is similar to the finding of local sensory nerve involvement in the cutaneous vascular effects of local warming (25, 38). Minson et. al (25) found that topical anesthetic reduced the cutaneous vasodilator response to local warming. Stephens et. al (38) likewise inferred participation of sensory nerves through comparison of the response to local warming at control sites with those at sites pretreated with capsaicin cream for chemical excitation of warm sensitive nociceptors. The vasodilator patterns differed when based on the local temperature but no longer differed when the basis was the perceived temperature (38). The inference is that the vasodilation with local warming is, at least in part, dependent on afferent activity of warm sensitive nociceptors.
Despite this similarity in the involvement of afferents in the cutaneous vascular responses to local cooling and local warming, we do not feel that this reflects a continuum of the same mechanism. We reach this conclusion because only in the case of local cooling does the afferent activity exert its effect through sympathetic nerves. There is no evidence that the vasomotor response to local warming has the same dependence on the cutaneous vasoconstrictor system (31).
Cold receptors are relatively rapidly adapting, with a large initial response followed by a lower steady-state firing rate still elevated from the baseline, graded with cooling intensity and with the rate of cooling (15, 22, 32, 35). In those studies of cold receptor activity, a reduction of 5°C was carried out over 10–15 s, much shorter than the 5 min required in the present study for a similar reduction in local temperature. Thus it seems likely that the response here to local cooling reflects more the steady state than the initial or rate-dependent responses by the afferents.
Figure 6 shows our working model of the mechanism of how local cooling exerts its effects on the cutaneous circulation as indicated by this study. These effects fall into the categories of the first few minutes and longer-term responses. The early vasoconstrictor response involves stimulation of cold sensitive receptors that, in addition to conveying the thermal information centrally, also act on sympathetic vasoconstrictor nerves locally to stimulate release of norepinephrine to cause the initial vasoconstriction. Removal of either sensory or sympathetic elements causes a reversal of that initial vasoconstriction to a significant vasodilation. This vasodilator response is, therefore, nonneural and is usually masked in intact areas by the vasoconstrictor response, although it can be revealed in intact areas with a more intense cooling stimulus (31). This vasodilation in areas of skin without intact sensory or autonomic function is replaced over the next 30 min or more by a vasoconstriction that is also apparently nonneurogenic because it requires neither sensory nor sympathetic nerves.
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2-receptors to norepinephrine while reducing that of 1-receptors, the latter effect being buffered in some tissues through receptor reserve (2, 6, 9–10, 14, 24, 41). These effects on adrenergic receptors occur in the face of reduced synthesis and release of norepinephrine from sympathetic nerve endings and a general inhibition of the contractile process (4, 10, 41). Apparently, in vivo, the tendency to inhibit norepinephrine release is countered by the local reflex to stimulate such release. The data from the present study do not distinguish among spinal, supraspinal, or purely local reflexes. In that regard, Pérgola et al. (31) found that nerve block proximal to and outside of the site of local cooling was without measurable effect on the vasoconstrictor response to direct cooling. This observation suggests that spinal or supraspinal reflexes do not contribute importantly to the response and that the elements illustrated in Fig. 6 are localized to the small area of skin subjected to the local cooling.
Could the longer-term vasoconstrictor response also be of neurogenic origin? Such might result from a lower sensitivity of some cold sensitive afferents to local anesthesia (11) or, similarly, from deeper cold receptors being beyond the penetration of the local anesthesia (16). These are important questions and require further investigation. We consider that possibility to be unlikely for two central reasons. First, the longer-term response persisted in the studies with bretylium and with yohimbine-propranolol. This shows that the sympathetic nerves are not involved in that later vasoconstriction, although the possibility of an additional more direct influence of sensory nerves on vascular smooth muscle cannot be excluded by these data. Second, cold perception was blocked by the local anesthetic, suggesting at least that all important neural cold sensitivity had been removed. Indeed, it may be that the longer-term vasoconstrictor response is independent of sympathetic neural function even in intact skin, replacing the initial, sympathetically mediated response as it is inhibited by the cooling.
The mechanisms for the nonneurogenic vasodilator and vasoconstrictor components of the responses to direct cooling are unknown. They may involve the effect of cold on smooth muscle energetics, blood viscosity, or endothelial function. Given that the early vasodilator response is transient, it is tempting to speculate that it is mediated through a depletable intermediate, whereas the vasoconstriction later in local cooling is more closely related to the direct effect of temperature on smooth muscle function or on plasma. However, these notions have yet to be tested.
We were surprised that local anesthetic failed to block sympathetic nerves. The components of Emla cream, lidocaine and prilocaine, would be expected to interfere with nerve conduction for all small myelinated or unmyelinated fibers, including vasoconstrictor fibers. It may be that those fibers are deeper than the topical anesthetic penetrates, whereas the sensory nerves are more superficial and within that depth of penetration (15). Indeed, our original design was to use the reflex vasoconstrictor response to cooling to test the effectiveness of the local anesthetic, but we were not able to document blockade of that response. However, this has the value of providing a method of selective removal of sensory processes from a selected area of skin while leaving sympathetic function intact. The reverse is achieved through blockade of transmitter release from sympathetic vasoconstrictor fibers with bretylium or the postsynaptic blockade of adrenergic receptors with yohimbine and propranolol.
The vasodilator response that occurred early in cooling at sensory or sympathetically blocked sites had a large variance, especially with pretreatment with Emla cream. We do not know the origin of this variance, although preliminary data from our laboratory show the rate of cooling to be an important determinant of the level of vasodilation in those areas (42). Although the vasodilator response was statistically significant at sites pretreated with Emla, bretylium, or yohimbine-propranolol, the degree of vasodilation was not statistically significantly different among sites (P > 0.06), despite the difference in the mean response. This bears further investigation.
In summary, we explored sympathetic and sensory roles in the cutaneous vascular response to mild local cooling. We found the immediate vasoconstrictor response to require both intact sensory function and intact sympathetic function whereas the longer-term vasoconstriction appears to have nonneuronal mechanisms. Nonneuronal mechanisms also generate an initial vasodilation, which is manifest when either sensory or sympathetic nerves are blocked. Thus the relatively simple vascular response to direct local cooling of the skin is manifest through a complex combination of sensory, autonomic, and direct effects, involving effects on receptor translocation, transmitter secretion and vascular smooth muscle contractile function.
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GRANTS |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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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REFERENCES |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
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2C-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol Heart Circ Physiol 278: H1075–H1083, 2000.-adrenoceptors in the cutaneous vasculature. Am J Physiol Heart Circ Physiol 273: H1038–H1043, 1997.-Adrenoceptors and cold-induced vasoconstriction in human finger skin. Am J Physiol Heart Circ Physiol 255: H1000–H1003, 1988.2-adrenoreceptor. Pharmacol Rev 35: 143–180, 1983.[ISI][Medline]
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