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. 1998 Mar 1;507(Pt 2):603–610. doi: 10.1111/j.1469-7793.1998.603bt.x

Vasodilator component in sympathetic nerve activity destined for the skin of the dorsal foot of mildly heated humans

Junichi Sugenoya 1, Satoshi Iwase 1, Tadaaki Mano 1, Yoshiki Sugiyama 1, Tokuo Ogawa 1, Tetsunari Nishiyama 1, Naoki Nishimura 1, Tomomi Kimura 1
PMCID: PMC2230797  PMID: 9518717

Abstract

  1. Skin sympathetic nerve activity (SSNA) was recorded in seven male subjects from the peroneal nerve by microneurography, and the temporal correspondence of spontaneously occurring SSNA bursts with vasodilatation and sweating responses on the dorsal foot was studied during a mild body heating at rest.

  2. Some SSNA bursts were followed by a sweat expulsion with a latency of 2.4 ± 0.4 s, and some bursts by a transient vasodilatation with a latency of 2.2 ± 0.4 s (means ± s.d.). SSNA bursts followed both by a sweat expulsion and by a vasodilatation response (Type 1), those followed only by a sweat expulsion (Type 2) and those followed only by a vasodilatation response (Type 3) were 70 %, 10 % and 1 % of the total bursts examined, respectively.

  3. For Type 1 bursts, there was a significant, but weak linear relationship among the burst amplitude, the amplitude of the corresponding vasodilatation and the amplitude of the corresponding sweat expulsion.

  4. It was concluded that SSNA contains vasodilatory activity which is synchronous with sudomotor nerve activity. The results suggest that such vasodilatory activity contributes to sustaining the sweat gland function by supplying sufficient blood.

In the human hairy skin, vasodilatation is achieved largely by an active mechanism although the release of vasoconstrictor nerve activities is partly involved (Roddie, 1983). Many investigations so far performed indicate that active vasodilatation is closely linked with sweating (Fox & Hilton, 1958; Allwood, Barcroft, Hayes & Hirsjärvi, 1959; Love & Shanks, 1962; Brengelmann, Freund, Rowell, Olerud & Kraning, 1981; Sugenoya, Ogawa, Imai, Ohnishi & Natsume, 1995). However, whether active vasodilatation is mediated by sudomotor nerve fibres or by vasodilator nerve fibres has not been solved.

Lundberg et al. (1989) have observed on the hairy skin of the foot an initial transient blood flow increase followed by a sustained decrease during the electrical stimulation of the sympathetic chain. Blumberg & Wallin (1987) have also demonstrated that transient vasodilatation is elicited on the dorsum of the foot by intraneural stimulation of the superficial peroneal nerve. These findings at least suggest that cutaneous active vasodilatation is mediated by the sympathetic nervous system.

Skin sympathetic nerve activity (SSNA) can be recorded with a microelectrode inserted percutaneously into a skin nerve fascicle. It is known that SSNA occurs as multi-unit bursts which involve sudomotor, vasoconstrictor and pilomotor activities (Bini, Hagbarth, Hynninen & Wallin, 1980; Sugenoya, Iwase, Mano & Ogawa, 1990). If cutaneous active vasodilatation is mediated by the sympathetic nervous system, SSNA should have a vasodilatory component. The present study examines whether such a component can be detected in SSNA, and, if so, whether it is related to sweating activity.

We recorded SSNA from the peroneal nerve, which innervates the dorsum of the foot. The temporal correspondence of SSNA bursts in the peroneal nerve with sweat and vasodilatory responses on the dorsal foot was analysed. Since a major mechanism for vasodilatation is active vasodilatation on the dorsal foot (Roddie, 1983), it is expected that SSNA in the peroneal nerve contains the activity associated with active vasodilatation.

METHODS

Subjects

Seven healthy male volunteers, aged 22–28 years (mean ± s.d., 24 ± 2.5 years), were informed of the purpose and the protocol, and gave their consent to the experiment. The study was approved by the Human Research Committee of the Research Institute of Environmental Medicine, Nagoya University.

Experimental protocol

Experiments were performed in a noise-proof room where the ambient temperature (Ta) and humidity were controlled. The subject, wearing shorts and a short-sleeved cotton shirt, entered the room at an Ta between 25 and 28°C (relative humidity, 40 %), and assumed a supine position on a bed made of a metal frame covered with a rubber cushion. A sweat capsule and a probe for the flowmetry were attached close to each other on a site of the central part of the dorsal foot. Skin sympathetic nerve activity (SSNA) was recorded at the popleteal fossa from the peroneal nerve. The recording of SSNA and the measurements of sweat and cutaneous blood flow rates were made on the ipsilateral side of the body.

After the control recording was made for 20 min, Ta was elevated to various levels between 32 and 40°C. Subsequently, the trunk and the thigh were wrapped with blankets (Blanketrol®, Cincinnati Sub-Zero, Cincinnati, OH, USA), which were perfused with hot water regulated at 43°C until a mild generalized sweating was induced. Tympanic temperature (Tty) was recorded with a thermistor (ST-21S, Sensor Technica, Seto, Japan).

Recording of skin sympathetic nerve activity

A tungsten microelectrode with a tip diameter of 1 μm and an impedance of 3–5 MΩ was inserted percutaneously into the skin fascicle of the peroneal nerve. Minor adjustments of microelectrode position within the fascicle were made until SSNA was encountered. SSNA was identified according to the following criteria (cf. Bini et al. 1980; Okamoto, Iwase, Sugenoya, Mano, Sugiyama & Yamamoto, 1994): it consists of spontaneous, irregular burst activity that is not synchronous with cardiac beat; such bursts are evoked reflexly by mental stress, sensory stimuli or deep breath, which are largely followed with a constant latency of 2–3 s by a sweat expulsion or a reduction of cutaneous blood flow. SSNA signals were amplified with a high input-impedance preamplifier (DAM-6A, World Precision Instruments, Hamden, CT, USA), processed with band-pass filters (500-5000 Hz) (E-3201A, NF Circuit Design, Yokohama, Japan) and stored in a magnetic data recorder (KS616U or PC116, Sony-Magnescale, Tokyo, Japan), monitoring on a storage oscilloscope (5113, Tektronix, Beaverton, OR, USA) and on a loudspeaker. The processed signals were then full-rectified, integrated with a time constant of 0.1 s and recorded as a mean voltage neurogram on a thermal chart recorder (Recti-Horiz, NEC-San-ei, Tokyo, Japan) at a paper speed of 0.5 cm s−1.

Measurement of sweat rate

Sweat rate was measured with a ventilated capsule equipped with a capacitance hygrometer (HMI-23, Vaisala, Helsinki, Finland). A sweat capsule covering an area of 1.3 cm2 was mounted on the test skin, and was ventilated with dry nitrogen at a rate of 0.3 l min−1. The humidity sensor was placed 3 cm down from the capsule outlet. The delay of sensing (estimated to be 0.04 s) was adjusted.

In four experiments pilocarpine delivered in 0.1 ml at a concentration of 10−5 g ml−1 was administered intracutaneously at the skin area beneath the capsule in the dorsal foot. The agent was administered prior to the attachment of the sweat capsule. Cholinomimetic agents such as pilocarpine can potentiate sweat production to visualize subthreshold sweat expulsions (Ogawa & Bullard, 1972), which are the premature responses elicited by weak sudomotor nerve activity during a mild thermal stress.

Measurement of cutaneous blood flow

Cutaneous blood flow was measured by means of laser-Doppler flowmetry (LDF). LDF instruments (ALF21, Advance, Tokyo, Japan) were used with the shortest time constant of 0.1 s. LDF probes, with a glass fibre opening distance of 0.9 mm, were held by a rubber holder, which was attached to the skin with adhesive tape. A contact medium for ultrasonic transmission was applied between the skin surface and the face of the probe, so as to minimize the influence of the sweat expelled beneath the probe. LDF data were displayed on the chart recorder and stored in the data recorder with the other parameters.

Blood flow curves were smoothed to eliminate the fast component associated with cardiac pulsation. For this purpose mid-points between the peak and the trough of pulse component were first obtained. The moving average of these points was then calculated using a weighting ratio of 0.25:0.5:0.25, and a smoothed blood flow curve was reconstructed by fitting the averaged points with a spline function.

Analysis

Definition of SSNA burst

Spontaneously occurring SSNA bursts that have an amplitude greater than 10 % of the maximum in the experiment were examined. When two SSNA bursts occur at a short interval, the elicited responses are often fused to each other so that two effector responses may not be separated from one another. In the present study, therefore, SSNA bursts that occurred earlier than 1.5 s after the preceding burst were excluded from the analysis of effector response. These bursts, defined as unclassified bursts, were approximately 9 % of total SSNA bursts examined. The onset of SSNA burst was defined as the steepest point of the upstroke.

Identification and quantification of sweat and blood flow responses

Sweat expulsion characterized by a transient, pulsatile increase in sweat rate was identified as a sweat response, according to our previous study (Sugenoya et al. 1990). Similarly, a transient, pulsatile increase in blood flow was identified as a vasodilatation response, as has been reported before (Sugenoya et al. 1995). In the present study sweat expulsions that have an amplitude greater than 2 % of the maximum in the experiment were used as an effective sweat response, and blood flow increases that have an amplitude greater than 5 % of the maximum were used as an effective vasodilatation response. The amplitude of sweat and vasodilatation responses was measured as the maximum of the vertical distance from the baseline to the curve. The baseline was determined tentatively as a line connecting the onset of the response to the point on the curve moved back by 1.0 s from the onset. The general criteria for detecting sweat and vasodilatation responses is based on the concept that the sweat and blood flow curve is constructed by temporal summation of successive transient responses that occurred at various intervals and with various amplitudes. Individual sweat and vasodilatation responses were defined as a convexity of the curve, and thereby the onset of the response was determined as an inflection point at which the slope of the tangent line discontinuously increases. Thus, it should be noted that when two responses are fused to each other a smaller one may produce a small hump on the upstroke or on the downstroke of the larger one (for example, the second and the fourth vasodilatation responses in Fig. 1). Such a small hump should also be recognized as an effective response even if it does not form a peak.

Figure 1. Response pattern of sweat and cutaneous blood flow to SSNA.

Figure 1

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Sweat rate and cutaneous blood flow rate recorded on the dorsal foot; skin sympathetic nerve activity (SSNA) obtained from the peroneal nerve. Tty = 37.10 °C. Blood flow rate is represented by the original tracing and by the curve smoothed with spline interpolation. SSNA is represented by a mean voltage neurogram. Arrows indicate the onsets of sweat and vasodilatation response. SSNA bursts marked by an open circle are followed by both a sweat and a vasodilatation response (Type 1 bursts); those marked by an asterisk are the unclassified bursts. See the text for the classification.

Collection of data

Tympanic temperature data were collected every 1 min. The rate of SSNA burst were evaluated for 10 s.

Neuro-effector relationship

For estimating the relationship between the SSNA amplitude and the amplitude of sweat and vasodilatation responses (Fig. 4), responses which appeared to be fused were not used since the amplitude of such fused responses was usually difficult to be estimated precisely.

Figure 4. Neuro-effector relationships.

Figure 4

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Interrelationship of the amplitude among SSNA burst, vasodilatation response and sweat response. Data from a single subject.

Statistical analysis

The linear regression analysis and Student's unpaired t test were used. Data are expressed as means ± s.d.

RESULTS

Sweat responses

Approximately 85 % of total SSNA bursts examined were followed by a sweat expulsion with a fixed latency (Fig. 1). The latency was 2.4 ± 0.4 s (between-subject mean in seven subjects). Figure 2A shows twenty strips of sweat rate change from a single subject each obtained during 15 s after a SSNA burst rose (time 0). In sixteen strips a sweat expulsion rose 2.1 s (dotted line) after the onset of SSNA burst. In most strips some other expulsions rose hereafter in response to the later bursts that are shown by small dots. Such a correspondence of SSNA burst with sweat expulsion was consistently noted for populations of SSNA bursts in each subject.

Figure 2. Sweat and cutaneous blood flow response to SSNA burst.

Figure 2

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Sweat (A) and cutaneous blood flow (B) curves triggered at the onset of SSNA burst; the left end of each curve indicates the onset of SSNA burst (time 0). These curves are obtained for twenty SSNA bursts that occurred during 3 min in a subject. Small dots on the curve represent the time at which SSNA bursts occurred. The sweat and blood flow curves shown by same numerals correspond with each other. The mean curves are delineated by averaging the twenty response curves.

Cutaneous blood flow responses

The predominant response of cutaneous blood flow in the dorsal foot during mild body heating was the vasodilatation response, as we reported before (Sugenoya et al. 1995). These vasodilatation responses were essentially similar in shape to sweat responses although the former were a little prolonged in duration and delayed in peak.

Approximately 70 % of total SSNA bursts examined were followed by such a putative vasodilatation response (Fig. 1). Thus, the correspondence of SSNA burst with vasodilatation response was less consistent than that with sweat response (Fig. 2B). Figure 2B also demonstrates that vasodilatation responses, if they occurred, were more variable in latency than the sweat responses. Nevertheless, the mean blood flow curve (n = 20, bottom curve) distinctly depicted a rise of blood flow at a latency of 2.5 s (dotted line). For all subjects the latency was 2.2 ± 0.4 s (between-subject mean in seven subjects). There were no other populations of SSNA bursts which were followed by the vasodilatation responses with a different latency.

Classification of SSNA bursts

Individual SSNA bursts in the peroneal nerve were divided into four types according to whether they were followed by a sweat response and whether by a vasodilatation response on the dorsal foot, as follows: Type 1, the burst followed by both a sweat and a vasodilatation response (Fig. 1); Type 2, the burst followed only by a sweat response (Fig. 3); Type 3, the burst followed only by a vasodilatation response (Fig. 3); Type 4, the burst followed neither by a sweat nor by a vasodilatation response (Fig. 3).

Figure 3. Classification of SSNA burst according to sweat and cutaneous blood flow response.

Figure 3

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The numerals below each burst indicate the type of SSNA burst (Type 1 to 4). Arrows indicate the onset of sweat and vasodilatation responses: the marks × denote the lack of the response. Tty = 37.10 °C. See the text for the classification.

Of the SSNA bursts occurring during a mild thermal stress of which Tty was between 36.5 and 37.1°C and the rate of SSNA burst between 12 and 19 min−1, approximately 70 % belonged to Type 1, 10 % to Type 2, 1 % to Type 3, 10 % to Type 4 and 9 % to unclassified bursts (Table 1). Of the SSNA bursts excluding the unclassified bursts, 75 % belonged to Type 1, 11 % to Type 2 and 2 % to Type 3. The individual difference in the proportion of burst type was minimal in the present thermal condition.

Table 1.

Classification of SSNA bursts

Subject Type 1 (%) Type 2 (%) Type 3 (%) Type 4 (%) Unclassified (%) n Burst rate (min−1) Tty (°C)
1 72.3 10.8 3.0 7.7 6.2 65 14.6 37.10
2 65.5 10.3 0.0 13.8 10.3 29 16.5 37.03
3 71.9 12.5 0.0 9.4 6.3 32 12.3 37.03
4 66.7 14.8 0.0 7.4 11.1 27 12.7 36.82
5 62.9 5.7 2.9 11.4 17.1 35 18.5 36.50
6 70.0 7.5 0.0 17.5 5.0 40 13.7 36.45
7 67.9 11.3 1.9 7.5 11.3 53 14.5 36.78
Mean 68.7 10.3 1.4 10.3 9.3 281 14.7 36.82
(75.6) (11.4) (1.6) (11.4)
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Values in parentheses are percentages calculated omitting the unclassified bursts.

Type 1 bursts, constituting the largest proportion of all types, are defined as sudomotor bursts which also induced a vasodilatation response. The amplitude of Type 1 burst was linearly related to the amplitude of the corresponding vasodilatation response, but the relationship was not so strong although significant in any subject (range of r, 0.552–0.623; P < 0.05; Fig. 4A). Further, this relationship was weak compared with that between the burst amplitude and the amplitude of the sweat response (range of r, 0.693–0.841; P < 0.05; Fig. 4B). The relationship between the amplitude of sweat expulsion and that of the corresponding vasodilatation response was also weak although significant (range of r, 0.484–0.768; P < 0.05; Fig. 4C).

Type 2 bursts are defined as sudomotor bursts which failed to induce any detectable vasodilatory response. Type 2 bursts occurred at significantly shorter intervals after the preceding burst than Type 1 bursts (3.8 ± 0.9 s vs. 6.0 ± 1.2 s between-subject means in seven subjects, P = 0.012). Furthermore, the amplitude of Type 2 bursts was significantly smaller than that of Type 1 bursts (20.4 ± 9.2 vs. 28.6 ± 13.4 between-subject means in seven subjects, P = 0.004).

Type 3 bursts are defined as the bursts which induced a vasodilatory response alone. Although this type of burst was too rare to be characterized, there was a tendency for the burst amplitude to be relatively small, and the corresponding vasodilatation response was also small. The latency from the burst to the corresponding vasodilatation responses varied rather greatly, as compared with Type 1 or Type 2 burst.

Type 4 bursts are defined as the bursts which induced neither sweat nor vasodilatation response. Type 4 bursts tended to have a smaller amplitude and a longer duration relative to the amplitude. Type 4 bursts were sometimes followed by a small decrease of blood flow on the dorsal foot, especially when they occurred successively at extremely short intervals (not illustrated).

DISCUSSION

The main result of the present study is that 75 % of total SSNA bursts examined for classification were followed by a transient vasodilatation response as well as a sweat response (Type 1 burst) in the dorsal foot during a mild thermal stress at rest. Of the SSNA bursts which were followed by a sweating response, 87 % (Type 1/[Type 1 + Type 2]) were also followed by a vasodilatation; only 13 % (Type 2/[Type 1 + Type 2]) were not followed by any detectable vasodilatation.

The results confirm that skin sympathetic nerve activity contains vasodilatory activity, but it was not determined whether this activity is caused by sudomotor nerve fibres (Fox & Hilton, 1958; Lundberg, Änggård, Fahrenkrug, Hökfelt & Mutt, 1980) or by specific vasodilator nerve fibres. If the latter is the case, the vasodilator nerve fibres should be activated concomitantly with sudomotor nerve fibres under the similar thermal conditions (Nordin, 1990; Sugenoya et al. 1995; Johnson & Proppe, 1996).

When vasodilatation by an active mechanism and vasoconstriction by a vasoconstrictor nerve mechanism occur simultaneously in the skin, blood flow rate may cancel each other out so that the vasodilatation response may be underestimated or masked. Although vasoconstriction activity is relatively weak in most hairy skin areas (Roddie, 1983) it really exists on the dorsal foot during mild body heating (Okamoto et al. 1994; Sugenoya et al. 1995). This implies that the underestimation or masking of the vasodilatation response might have occurred in the present study. When the vasodilatation response has been totally masked, the original Type 1 burst would be misidentified as a Type 2 burst. Furthermore, when the vasodilatation response, specifically the initial part of it, has been partially masked, the onset of the vasodilatation response would be taken to be delayed.

Mechanism of the sudomotor nerve system

The hypothesis that vasodilatation and sweating are controlled through common sudomotor nerve fibres was proposed by Fox & Hilton (1958). They assumed that bradykinin, which is formed when sweat gland cells are activated by sudomotor nerve impulses, dilates the skin vasculature. However, the evidence which supports this mechanism is still lacking. An alternative mechanism proposed by Lundberg, Hökfelt, Schultzberg & Uvnäs-Wallensten (1979) is that vasodilatory neuropeptides which are released at the terminals of the cholinergic postganglionic fibres supplying the sweat glands act as vasodilatory agents.

A number of vasodilative neuropeptides including vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), atrial natriuretic polypeptide (ANP) and substance P have been identified in the terminals of the sympathetic fibres innervating the human eccrine glands (Hartschuh, Weihe & Reinecke, 1983; Hartschuh, Reinecke, Weihe & Yanaihara, 1984; Vaalasti, Tainio & Rechardt, 1985; Johansson, 1986; Tainio, Vaalasti & Rechardt, 1987; Savage, Brengelmann, Buchan & Freund, 1990). The existence of some of these neuropeptides (VIP, CGRP, somatostatin) has also been demonstrated in the cell bodies of human paravertebral sympathetic ganglia, suggesting the sympathetic origin of the peptide-containing fibres governing the eccrine glands (Schmitt, Kummer & Heym, 1988). It has been proposed that these neuropeptides co-operate with acetylcholine in controlling the sweat gland function, acetylcholine causing sweat secretion, the neuropeptides increasing local blood flow (Lundberg et al. 1979).

In the present study most SSNA bursts (Type 1 bursts) produced a vasodilatation response as well as a sweat response. The presence of such Type 1 bursts is entirely compatible with a hypothesis from the peptide mechanism that sudomotor nerve activation elicits the concomitant release of acetylcholine and the neuropeptides at the nerve terminals. By assuming the general characteristics of the sudomotor nerve system such that the threshold for vasodilatation is higher than that for sweat response, the presence of the Type 2 burst is fully understood. Hereupon, the threshold for effector response may involve the following two processes: the threshold neural activity for releasing the transmitter substance and the threshold amount of the released substance for producing the effector response. Moreover, the difference in the sensitivity for detecting effector responses may be involved: it is likely that blood flow measurement is less sensitive than sweat rate measurement. The evidence supporting the difference in threshold is the finding that the amplitude of Type 2 bursts was significantly smaller than that of Type 1 bursts.

Mechanism of vasodilator nerve system

Specific vasodilator nerve fibres have not been demonstrated in human skin, but the presence of such fibres has been suggested. Some investigations indicated that active vasodilatation and sweating responses are not necessarily parallel during exercise (Crandall, Musick, Hatch, Kellogg & Johnson, 1995) or during baroreceptor unloading (Solack, Brengelmann & Freund, 1985; Kellogg, Johnson & Kosiba, 1990). Accordingly, a model has been proposed in which vasodilator nerves and sudomotor nerves are separate, and these nerves would be activated in a similar pattern by thermal input under a common central thermoregulatory control, whereas they would be activated differentially by non-thermal factors (Johnson & Proppe, 1996).

The relationship between the burst amplitude and the amplitude of the vasodilatation response was not so strong (Fig. 4A, r = 0.552–0.623) as to establish a reliable neuro-effector relationship. Furthermore, the parallelism between vasodilatation and sweat response was incomplete as indicated by the presence of Type 2 or Type 3 bursts. These observations appear to be favourable for the separate vasodilator nerve mechanism. However, these observations can be explained on the basis of the sudomotor nerve mechanism as having occurred through the errors in identifying or measuring the vasodilatation response caused by the cancellation of blood flow due to concomitant vasoconstriction. It is our view that although there are minor observations suggesting the dissociation between sweating and vasodilatation activities we have no direct evidence supporting the separate vasodilator nerve mechanism.

Significance of vasodilatory activity in sympathetic outflow

Two physiological roles are assumed for the pulsatile vasodilatation response synchronous with sweat gland activation: first, the role of maintaining the sweat gland function by securing blood supply, and second, the role as an effector response of active vasodilatation. The first role has been suggested as a role of vasodilative peptide by a few authors (Yamashita, Ogawa, Ohnishi, Imamura & Sugenoya, 1987; Yamashita, Ogawa, Sugenoya & Ohnishi, 1989), who observed that intracutaneous injection of such a peptide enhanced the methacholine-induced sweat secretion. The second role of our pulsatile vasodilatation responses is not confirmed with the present data, but is predicted since we analysed previously the vasodilatation response synchronous with sweat expulsion observed in the dorsal foot during a mild body heating, and have demonstrated that the rate of such a vasodilatation response is a linear function of core temperature (Sugenoya et al. 1995).

It is concluded that vasodilatory activities detected in SSNA from the peroneal nerve contribute, by eliciting pulsatile vasodilatation on the skin of the dorsal foot, to sustaining the sweat gland function. It remains to be studied whether such activities are associated with cutaneous active vasodilatation.

Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research (C) (no. 07670093), from the Ministry of Education, Science, Sports and Culture of Japan.

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