Clinical Hemorheology and Microcirculation 45 (2010) 365–374 DOI 10.3233/CH-2010-1320 IOS Press
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Regular physical activity alters the postocclusive reactive hyperemia of the cutaneous microcirculation ˇ Helena Lenasi∗ and Martin Strucl Institute of Physiology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
Abstract. Regular physical activity leads to increased endothelium-dependent vasodilatation. Postocclusive reactive hyperemia (PRH) is a transient increase of blood flow after the release of an arterial occlusion and has been used as a clinical tool to estimate endothelial function. The aim of our study was to assess the potential effect of regular physical training on PRH of skin microcirculation. Skin blood flux was estimated by laser-Doppler fluxmetry (LDF) in two groups of subjects: 12 highly trained athletes and 12 age-matched sedentary controls. LDF was measured on two specific skin sites: volar aspect of the forearm (nonglabrous area) and finger pulp of the middle finger (glabrous area). After the release of a 3-min occlusion of the brachial artery, we determined the following indices of PRH: the time to peak (tpeak ), the maximal LDF (LDFpeak ), the recovery time (trec ), the area under the PRH curve (AUC). Baseline LDF did not differ between the trained and sedentary subjects in either site. On the forearm, we found no significant differences in either PRH parameter. On the contrary, on the finger pulp, there were statistically significant differences in the tpeak and the AUC (p ≤ 0.05). The results show an altered PRH response of skin microcirculation in the finger pulp in the trained subjects. We may speculate that this could be the result of an increased endothelial vasodilator capacity. Further, the potential adaptations of the endothelium differ between the glabrous and nonglabrous skin sites. Keywords: Skin microcirculation, laser–Doppler fluxmetry, postocclusive reactive hyperemia, endurance, endothelium
1. Introduction Skin microcirculation has gained increasing interest over the last decades as it is easily accessible and has been proposed to reflect generalized microvascular function [21, 27]. As skin is the main organ for heat elimination from the body, its blood flow has been estimated to vary between 300 ml/min/kg up to 8 l/min/kg in the settings of strenous exercise in a hot environment [23, 25]. Moreover, it has been shown that endurance-trained subjects have a higher skin blood flow at any given level of workload and core temperature, when compared with matched sedentary controls [12, 20, 38, 41]. It is thus obvious that the regulation of skin blood flow is a delicate and complex phenomenon that comprises a well coordinated interplay of central as well as local mechanisms [24–26, 39]. One of the most important local mechanisms is endothelium that in physiological conditions releases vasodilators and vasoconstrictors in a balanced way. Furthermore, the control of skin blood flow is strongly site-dependent: acral parts (glabrous areas) contain arteriovenous anastomoses (AVAs) that represent a functional entity for heat elimination and are predominately under symphathetic neural influence [23, 45, 47]. On the other hand, nonglabrous areas with no AVAs receive also vasodilatory symphathetic nerve fibres with no uniformely confirmed ∗
Corresponding author: Helena Lenasi, MD, Institute of Physiology, Medical Faculty, Zaloˇska 4, 1000 Ljubljana, Slovenia. Tel.: +386 1 543 7513; Fax: +386 1 543 7501; E-mail:
[email protected]. 1386-0291/10/$27.50 © 2010 – IOS Press and the authors. All rights reserved
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vasodilator that may well be nitric oxide (NO) [23, 26, 39]. To which extent endothelium contributes to the regulation of vascular tone and vasodilatation in glabrous and nonglabrous skin areas has not been extensively studied [23, 26, 33, 39]. Skin microcirculation and endothelial function in general have been shown to be impaired in many cardiovascular diseases [6, 15, 17, 19, 30] and in hyperlipoproteinemia [30], in diabetes [5], some neurological diseases [40], in smokers [37], as well as with aging [2, 22, 36, 43]. One of the measures to improve endothelial dysfunction due to reduced NO bioavailability seems to be regular physical activity. Participation in regular aerobic training has confirmed an improvement of endothelium-dependent vasodilatation in many diseases such as hypertension [19], coronary heart disease [17] and diabetes [6] in the vascular beds of active tissues. It has also been shown in young [18, 28, 31, 42, 44] and older [2, 42] healthy trained subjects that endurance training is associated with an enhanced responsiveness of the cutaneous microcirculation to endothelium-dependent stimuli. Nevertheless, the results on the impact of endurance training on the endothelium-dependent vasodilatation, specially in skin microcirculation of healthy, are controversial [3, 7, 18, 28, 38, 42]. Also, the mechanisms of an enhanced cutaneous microvascular responsiveness induced by training remain unclear. Thus, establishing measures to preserve or improve endothelial function are of great clinical importance. One of the widely used clinical methods to evaluate endothelial function, that is easily applicable, is assessment of postocclusive reactive hyperemia (PRH) [8, 30, 49]. PRH is a transient increase of blood low after a temporal occlusion of the corresponding artery. Factors contributing to this phenomenon include vasodilators released from endothelium in response to increased shear stress as well as locally released metabolites accumulated in the ischemic tissue and myogenic component [9, 11, 32, 45, 49]. The aim of our study was therefore to assess the impact of training on the PRH of skin microcirculation in two representative measuring sites. We hypothesised that the endothelial vasodilator capacity, estimated by indices of PRH, might be increased in trained due to repetitively increased shear stress to which endothelial cells are exposed during bouts of aerobic exercise. We measured cutaneous blood flux in two groups of subjects with significantly different aerobic fitness by the use of laser Doppler fluxmetry (LDF) in the middle finger pulp (representative of glabrous area) and on the volar aspect of the forearm (nonglabrous area) before and after a 3-min occlusion of the brachial artery. 2. Methods 2.1. Subjects We recruited two groups of men: 12 endurance-trained cyclists who performed regular training (at least 15 hours of intense aerobic exercise weekly for many years) and were competing at a national level and 12 age-matched sedentary men who performed no regular exercise. The anthropometric characteristics and baseline blood pressure as well as the resting heart rate were assessed upon the arrival to our laboratory. All subjects were healthy normotensive nonsmokers and had been taking no medications nor had a family history of cardiovascular diseases. The study conformed to the Declaration of Helsinki and was approved by the National ethics commitee. All subjects gave written informed consent. 2.2. Measurements Subjects had abstained from food, caffeine-containing drinks and alcohol for at least eight hours prior to their attendance and were asked to refrain from strenous exercise for at least 24 hours. All experiments
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were performed in a temperature-controlled room (24 ± 1o C) in the forenoon with subjects laying in a supine position; prior to any measurements subjects lied for 30 min to acclimatize. Cutaneous microcirculation blood flux was measured by means of laser Doppler fluxmetry described elsewhere [8, 16, 31, 48]. A two-channel laser Doppler fluxmeter (Periflux 4001 Master, Perimed, Sweden) with a laser beam of 780 nm wavelength was used and the LDF data were expressed in arbitrary perfusion units (PU). Before the measurement, the device was calibrated for zero calibration. The LD probes were attached as follows: (1) to the finger pulp of the middle finger of the nondominant arm to assess the LDF in glabrous area and (2) to the volar aspect of the nondominant forearm, avoiding superficial veins to assess the LDF in the nonglabrous area. The sampling frequency was 500 Hz and the digitalized LDF signal was simultaneously transmitted to a personal computer for further analysis. At both measuring sites, skin temperature was continuously recorded locally by a digital thermometer (Peritemp PF4005, Perimed, Sweden). Arterial pressure of the digital artery was measured on the fourth finger (Finapress, Ohmeda 2300) and a standard ECG was continuously monitored. 2.2.1. Protocol 1 To assess the effect of acute exercise on LDF in glabrous and nonglabrous area. Only sedentary males participated in this protocol that was held on a separate occasion. We carried out this protocol to assess the extent of potential increase in skin perfusion in glabrous vs. nonglabrous site following acute bout of exercise. After obtaining baseline recordings of the LDF and skin temperature for 5 min at the two measuring sites (finger pulp and volar forearm), the LD probe holders were left in place and subject began cycling on a standard cycloergometer at a workload of 40 Watt that was gradually increased to a submaximal level, predicted from the estimated submaximal heart rate according to the subject’s age. The subject cycled at this workload for 20 min. Immediately after having stopped the exercise, the subject again lied in a supine position, the LD probes were fixed to the very same measuring sites as before exercise and LD fluxes and skin temperatures were traced as long as to reach the resting values. 2.2.2. Protocol 2 To assess the indices of postocclusive reactive hyperemia (PRH) in glabrous and nonglabrous area of the trained and the sedentary. After a 5-min baseline recordings of the LDF in the finger pulp and the volar forearm had been obtained, brachial artery was occluded to suprasystolic pressure with an inflatable arm cuff for three minutes. LDF was continuously monitored (biological zero). After three minutes, the cuff was released and the LDF was recorded as long as 5 min after returning to the baseline level. The following indices of PRH were determined: peak flow (LDFpeak ), defined as the maximal LDF after release of the occlusion, time to peak (tpeak ), defined as the time to reach LDFpeak after cuff deflation, the recovery time (trec ), defined as the total duration of PRH, i.e. the time in which the LDF returns to its baseline value, the area under the curve (AUC), defined as an integer of the PRH curve and reflecting perfusion debt repayment [30, 37, 49]. The representative LDF tracings of the two representative measuring sites following the release of an occlusion are presented in Fig. 1. 2.3. Assessment of physical fitness Physical fitness was evaluated on a separate occasion by measuring the resting heart rate and maximal oxygen consumption (VO2max ). VO2max was assessed by a maximal graded exercise test on a standard cycle ergometer with the initial workload of 40 Watt that was incrementally increased by 30 W in sedentary
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Fig. 1. Representative tracings of the postocclusive reactive hyperemia in the two sites: (A) middle finger pulp and (B) volar forearm. PRH was induced by a transient 3-min occlusion of the brachial artery. LDF, laser Doppler flux; PU, perfusion units, LDFpeak , maximal LDF after release of the occlusion; tpeak , time to peak; trecovery , recovery time (duration) of PRH; AUC, area under the curve.
and by 40 W in athletes every three minutes until exhaustion. During the test, heart rate was continuously recorded by electrocardiogram as well sphygmomanometric blood pressure of the brachial artery. Oxygen consumption and the CO2 content in the expired air were recorded via face mask by a gas analyser and respiratory exchange ratio (RER) was calculated. VO2max was defined as the mean of the two highest consecutive 30-s VO2 measurements that met the following criteria: attainment of the plateau of VO2 with increasing exercise intensity and RER exceeding 1.1. 2.4. Data acquisition and statistical analysis LDF data were analyzed off-line by the ‘Nevrocard LDDA’ acquisition system. The baseline LDF data reported are averaged over a 3-min period. The maximal LDF responses to acute exercise (protocol 1) were averaged over 10 s-intervals. As for the protocol 2, LDFpeak was expressed as a percentage increase over the baseline. The trec was obtained as the interception point of the fitted PRH curve and the average LDFbaseline line. AUC was calculated as an integer of the PRH response (sum of the averaged 1 sec-recordings of the LDF). The results are presented as group means ± SEM. The LDF increase over the baseline after the release of arterial occlusion in each subject was evaluated by ANOVA for repeated measurements. The paired or unpaired two-tailed Student’s t-test was used to compare the LDF data between rest and postexercise for each group and the parameters of PRH between the two groups, respectively. A p-value of less than 0.05 was accepted as statistically significant. 2.5. Reproducibility assessment To test the reproducibility of the method, baseline LDF and PRH-induced changes were recorded on two separate occasions at the same time of the day, under the same conditions in six subjects. These individual coefficients of variation were then averaged across subjects to provide overall estimates of intraindividual variability.
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3. Results Anthropometric characteristics and some baseline cardiovascular parameters of the subjects are shown in Table 1. The only significant difference between the sedentary and trained group was observed in the resting heart rate. Furthermore, the VO2max was significntly greater in the trained, as expected: 65 ± 1 ml/min/kg in trained and 41 ± 1 ml/min/kg in sedentary. Both latter parameters reflect an increased aerobic fitness level in the trained group. The baseline LDF as well as skin temperature did not differ in either measuring site between the trained and sedentary (t-test, Table 2). LD fluxes were significantly greater in the finger pulp compared to the volar forearm in both groups (Table 2). 3.1. The effect of acute exercise on LDF of glabrous and nonglabrous area Acute 20-min cycling at submaximal aerobic workload caused a significant increase in LDF in the finger pulp (glabrous area) as well as in the volar forearm (nonglabrous area) (p ≤ 0.01). Skin temperature increased by 1.5 ± 0.9o C. The increases of LDF in six sedentary subjects in response to exercise are Table 1 Anthropometric characteristics and some hemodynamic parameters of subjects
Age (years) Height (cm) Body weight (kg) psystol (mmHg) pdiastol (mmHg) Heart rate (beats/min) psystol-digital (mmHg) pdiastol-digital (mmHg)
Sedentary
Trained
24.9 ± 1.1 182.6 ± 1.4 76.9 ± 2.6 120.4 ± 2.0 80.9 ± 2.1 69.3 ± 3.6 102.2 ± 4.6 78.9 ± 2.80
22.6 ± 0.9 180.6 ± 2.2 79.5 ± 2.6 117.3 ± 2.5 77.3 ± 1.7 50.0 ± 2.5* 99.3 ± 4.3 74.3 ± 3.2
psystol , systolic blood pressure of the brachial artery; pdiastol , diastolic blood pressure of the brachial artery; psystol-digital , systolic blood pressure of the digital artery; pdiastol-digital , diastolic blood pressure of the digital artery; LDFbaseline , baseline LDF, PU, perfusion units. Results are mean ± SEM, n = 12. *p ≤ 0.05. Table 2 Baseline laser Doppler flux (LDF) and skin temperature in the finger pulp and on the volar forearm in trained and sedentary Volar forearm
LDFbaseline (PU) Tskin (◦ C)
Finger pulp
Sedentary
Trained
Sedentary
Trained
14.2 ± 2 32.2 ± 0.7
15.6 ± 1.7 32.6 ± 0.3
176 ± 20* 32.9 ± 0.3
202 ± 16* 33.4 ± 0.2
LDFbaseline , baseline LDF; PU, perfusion units; Tskin , temperature of the skin over the reperesenative measuring site. Results are mean ± SEM, n = 12. *p ≤ 0.01, finger pulp vs. volar forearm for the trained and for the sedentary group.
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presented in Fig. 2. Of note is a high variability of maximal LDF after exercise (the LDF increment ranged from 150% up to 700%). 3.2. The effect of fitness status on postocclusive reactive hyperemia in glabrous and nonglabrous area The release of a 3-min occlusion of the brachial artery caused a significant increase of LDF in the finger pulp and on the forearm in all subjects (Fig. 1). On the volar forearm none of the indices of PRH reached statistical difference between the groups of trained and sedentary (Table 3, t-test) although there was a trend toward statistical diference regarding the AUC (Table 3, p = 0.09, t-test). On the contrary, the tpeak and the AUC of PRH in the finger pulp significantly differed between the two groups. The tpeak was shorter in trained whereas the AUC significantly larger in the group of trained compared to the sedentary (Table 3, p ≤ 0.05, t-test). Other indices of PRH in the finger pulp did not reach a statistical difference. 450
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Fig. 2. LDF response to acute exercise in the glabrous and nonglabrous skin area. LDF was assessed on the finger pulp (glabrous area) and on the volar forearm (nonglabrous area) before (resting) and after 20-min acute submaximal exercise on cycloergometer. LDF, laser Doppler flux; PU, perfusion units; n = 6, *p ≤ 0.01, LDF in the volar forearm (empty bars) after vs. before exercise and LDF in the finger pulp (filled bars) after vs. before exercise. Table 3 Indices of postocclusive reactive hyperemia (PRH), as assessed on the volar forearm and in the finger pulp in the trained and sedentary after a 3-min occlusion of the brachial artery Volar forearm
LDFpeak (PU) tpeak (sec) trec (sec) AUC (PU*sec)
Finger pulp
Sedentary
Trained
Sedentary
Trained
52 ± 5 7.3 ± 0.6 62 ± 6 1260 ± 181
60 ± 9 8.1 ± 1.6 69 ± 5 1423 ± 195
374 ± 26 36 ± 5 143 ± 20 10527 ± 662
410 ± 36 29 ± 5* 164 ± 12 14560 ± 750*
LDF, laser Doppler flux; PU, perfusion units; LDFpeak , peak, maximal LDF; tpeak , time to rich LDFpeak ; trec , recovery time; AUC, area under the curve. Results are mean ± SEM, n = 12, *p ≤ 0.05, trained vs. sedentary.
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3.3. Reproducibility The intraindividual coefficients of variation were ranged between 3.3% and 41.2% (mean 19.9 ± 5%) for the baseline LDF and between 5.1% and 44.2% (mean 23.5 ± 6%) for the response to the release of the arterial occlusion.
4. Discussion The main finding of our study is that certain indices of the cutaneous PRH differ between sedentary and highly-trained healthy men in the finger pulp but not in the forearm. We may imply an enhanced vasodilator capacity of the finger pulp microcirculation induced by aerobic training. Further, the potential adaptations to physical conditioning as assessed by indices of PRH are probably different in glabrous and nonglabrous skin sites. To our knowledge, no study that applied laser Doppler fluxmetry and performed PRH to assess the microvascular reactivity simultaneously evaluated the impact of physical training on the reactivity of cutaneous microcirculation in the two representative measuring sites: glabrous and nonglabrous one. The indices of PRH in trained compared to sedentary in our study were different between the two distinct sites. Different responses of glabrous and nonglabrous skin have been already shown in acute static [46] and dynamic [47] exercise. Most studies assessed the impact of chronic training in the forearm skin as a representative of nonglabrous site and the results are not consistent. The study of Heylen showed an increased AUC and the recovery time of PRH and no changes in the time to peak and half time of PRH in highly trained windsurfers [18]. Nevertheless, they used a 5-min occlusion of the brachial artery in contrast to our 3-min occlusion. Vassalle and coworkers also showed an enhanced endothelium-dependent vasodilatation in trained that also correlated with the plasma levels of NO [42]. They attributed the higher post ischemic peak LDF in trained to an increased release of NO in trained [15, 17, 42]. The discrepancy to our study could hardly be attributed to any factor as the VO2max as well as the type of sports and the time of artery occlusion were comparable. Actually we also hypothesised to get an enhanced PRH in trained as we have shown that acute exercise in addition to the regions with AVAs, also significantly increases blood flow in the forearm skin. Moreover, there are reports that blood flow in the forearm skin microcirculation is increased in trained compared to sedentary exposed to the same level of exercise intensity [12, 20, 38, 41]. These observations may partly explain the fact that at the given internal temperature the treshold for heat elimination is lower in trained [23] and may well be the consequence of an endothelial adaptation. Contrary to our expectations and to the aforementioned studies [12, 20, 38, 41] we have shown no differences in either index of PRH in the forearm between the trained and the sedentary. Similar results in healthy were observed in the study of Colberg et al. [6]. The results are also in agreement with Boegli who also did not confirm differences in the peak LDF and AUC of PRH between trained and sedentary [3]. If we rely on the assumption that PRH could be considered as a measure of endothelial function [49], a possible explanation could be that the nonglabrous sites predominantly serving the nutritive blood flow are not subject to variation of blood flow due to thermoregulation to that extent as to induce changes in the responsiveness of endothelium. In the light of former observations [12, 20, 38, 41] and our results of acute exercise this seems less likely. Another explanation would be that mechanisms other than endothelial vasodilators predominate in PRH. It could be that the sedentary subjects
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accumulate more ischemic metabolites during the occlusion that strongly contribute to an increase of AUC; it is a well known phenomenon that the extraction of oxygen from blood due to adaptations of oxidative metabolism enzymes is better in trained compared to sedentary [13]. Further, the potential endothelial adaptation could be masked by an increase in oxidative stress induced by strenous exercise in highly trained [1, 14]. This seems less probably as it would likely affect also the reactivity of the finger pulp microcirculation. Last but not least athletes may exhibit an altered sensitivity of the vascular smooth muscle cells to endothelial vasodilators that, contrary to the observation of Boegli [3], we proposed in our previous study [31]. Nevertheless, these are only speculations that need further clarifications. As for the finger pulp we have shown that the time to peak was shorter and the AUC of the PRH larger in trained. This is the first study that assessed the impact of strenous aerobic training on the LDF response in the finger pulp to a 3-min occlusion of the brachial artery. We have already shown an increased AUC in the finger pulp of trained men after an 8-min occlusion of the digital artery [31]. Since it has been suggested that shorter times of occlusion more faithfully reflect the contribution of NO and thus endothelial component of PRH [35] we induced a shorter occlusion (of the brachial artery). We may speculate that an increased AUC of PRH in our study could be a consequence of an enhanced endothelium-dependent vasodilatation of the finger pulp microcirculation in the trained. Also, the shorter tpeak may reflect more rapid increase of LDF due to more vasodilators released from the endothelium as a consequence of increased shear stress caused by flow increment after the release of arterial occlusion. This may be due to NO, prostaglandins and endothelium-dependent hyperpolarizing factor. Namely, the exact contribution of each of these mediators to the PRH remains to be uncovered since there are no uniform results regarding this issue [7, 9, 11, 32, 45]. On the other hand, we can not exclude an adaptation of the central mechanisms, i.e. sympathetic nervous system. Yet, the two potential adaptations should not be regarded as separate phenomena: in fact there is an interplay between local and central mechanisms regulating vascular tone. It is known that NO acts on presynaptic ␣2 -adrenergic receptors on the sympathetic nerves [10]. NO is also suggested to be a signalling molecule to bring about coordinated increases in cutaneous vasodilatation and heat dissipation in skin [24–26]. Exercise training has been suggested to reduce sympathetic tone and supress the pressor response to adrenergic agents by increasing NO release from the endothelium [4]. The increased responsiveness of glabrous sites in trained can well be the consequence of an adjusted interplay between local and central mechanisms regulating blood flow in these areas. Our study has several limitations: it is cross-sectional and a prospective study may have been more relevant. Another pitfall is the small number of subjects included. It is worth to note that there were assumedly differences in the AUC in the forearm between trained and sedentary that did not reach statistical difference. Finally, there is a need to standardize the measures to evaluate PRH [8, 48, 49] as well as to reveal the strenght of each of the mechanisms contributing to PRH in human skin. Additional studies using supplementary methods such as newly improved high resolution ultrasound combined with fluorescence video angiography for the optimal assessment of perfusion in cutaneous, subcutaneous and deeper tissue layers [29, 34] would strenghten our results and make them more reliable. In conslusion, highly trained athletes exhibit a shorter tpeak and an increased AUC after a 3-min arterial occlusion in the finger pulp. This might point to an increased vasodilator capacity of the glabrous skin sites and may have clinical implications. The indices of PRH in the volar forearm are comparable between the trained and sedentary. This reflects different mechanisms of adaptation to exercise in glabrous and nonglabrous skin areas, at least with respect to PRH. Additional studies are needed to elucidate the control of skin blood flow in glabrous and nonglabrous sites as well as the exact mechanisms contributing to the cutaneous PRH.
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