Increase In Skin Blood Flow Research Articles

Effects of Frankincense and Myrrh essential oil on transdermal absorption in vitro of Chuanxiong and penetration mechanism of skin blood flow

The aim of this paper was to explore the effects of Frankincense and Myrrh essential oil on transdermal absorption in vitro of Chuanxiong, and to investigate the possible penetration mechanism of their essential oil from the perspective of skin blood perfusion changes. Transdermal tests were performed in vitro with excised mice skin by improved Franz diffusion cells. The cumulative penetration amounts of ferulic acid in Chuanxiong were determined by HPLC to investigate the effects of Frankincense and Myrrh essential oil on transdermal permeation properties of Chuanxiong. Simultaneously, the skin blood flows were determined by laser flow doppler. The results showed that the cumulative penetration amount of ferulic acid in Chuanxiong was (8.13±0.76) μg•cm⁻² in 24 h, and was (48.91±4.87), (57.80±2.86), (63.34±4.56), (54.17±4.40), (62.52±7.79) μg•cm⁻² respectively in Azone group, Frankincense essential oil group, Myrrh essential oil, frankincense and myrrh singly extracted essential oil mixture group, and frankincense and myrrh mixed extraction essential oil group. The enhancement ratios of each essential oil groups were 7.68, 8.26, 7.26, 8.28, which were slightly greater than 6.55 in Azone group. In addition, as compared with the conditions before treatment, there were significant differences and obvious increasing trend in blood flow of rats in Frankincense essential oil group, Myrrh essential oil group, frankincense and myrrh singly extracted essential oil mixture group, and frankincense and myrrh mixed extraction essential oil group when were dosed at 10, 20, 30, 10 min respectively, indicating that the skin blood flows were increased under the effects of Frankincense and Myrrh essential oil to a certain extent. Thus, Frankincense and Myrrh essential oil had certain effect on promoting permeability of Chuanxiong both before and after drug combination, and may promote the elimination of drugs from epidermis to dermal capillaries through increase of skin blood flow, thus enhancing the transdermal permeation amounts of drugs.

Tissue Blood Volume Parameters Measured by Continuous-Wave and Spatially Resolved NIRS Show Different Changes During Prolonged Cycling Exercise.

Near-infrared spectroscopy (NIRS) shows two types of tissue blood volume (BV) parameters: the total hemoglobin concentration (cHb; assessed by continuous-wave NIRS) and the normalized tissue hemoglobin index (nTHI; evaluated by spatially resolved NIRS). This study was performed to investigate the differences between cHb and nTHI, estimated by calibration using acute reduction of BV at the onset of exercise. Seven active male volunteers (age: 22 ± 4 years) performed a prolonged (60-min) cycling exercise test at 65% or 70% of the peak oxygen uptake. During the tests, cHb and nTHI from the vastus lateralis muscle were monitored. The two parameters were expressed relative to the resting value of 100% and the minimum value of 0% at the onset of exercise. The value of cHb started to increase after arriving at the minimum value and continued until the end of exercise. Similar to cHb, nTHI increased acutely from the lowest level, but the parameter remained almost unchanged from ~5 min throughout the test. Therefore, the two parameters interacted significantly. Moreover, in comparison with the same exercise duration, cHb was significantly higher than nTHI from the 28th min to the end of the test. These results suggest that cHb and nTHI in working muscle are not synchronized during prolonged exercise, especially after ~30 min. The differences between the two BV parameters are likely partly attributable to other factors, such as the increase in skin blood flow.

Acute vascular effects of carbonated warm water lower leg immersion in healthy young adults.

Endothelial dysfunction is associated with increased cardiovascular mortality and morbidity; however, this dysfunction may be ameliorated by several therapies. For example, it has been reported that heat‐induced increases in blood flow and shear stress enhance endothelium‐mediated vasodilator function. Under these backgrounds, we expect that carbon dioxide (CO 2)‐rich water‐induced increase in skin blood flow improves endothelium‐mediated vasodilation with less heat stress. To test our hypothesis, we measured flow‐mediated dilation (FMD) before and after acute immersion of the lower legs and feet in mild warm (38°C) normal or CO 2‐rich tap water (1000 ppm) for 20 min in 12 subjects. Acute immersion of the lower legs and feet in mild warm CO 2‐rich water increased FMD (P < 0.01) despite the lack of change in this parameter upon mild warm normal water immersion. In addition, FMD was positively correlated with change in skin blood flow regardless of conditions (P < 0.01), indicating that an increase in skin blood flow improves endothelial‐mediated vasodilator function. Importantly, the temperature of normal tap water must reach approximately 43°C to achieve the same skin blood flow level as that obtained during mild warm CO 2‐rich water immersion (38°C). These findings suggest that CO 2‐rich water‐induced large increases in skin blood flow may improve endothelial‐mediated vasodilator function while causing less heat stress.

Decreased Symptoms without Augmented Skin Blood Flow in Subjects with RLS/WED after Vibration Treatment.

Vascular disturbances leading to tissue hypoxia have been named as a possible cause for RLS/WED. Vibration to the whole body (WBV) in subjects with RLS/WED results in increased skin blood flow (SBF). The aims of this investigation were to (1) determine if a two-week treatment with WBV will decrease symptoms associated with RLS/WED and, (2) if so, determine if the mechanism for improvement in symptoms is related to an increase in SBF, as measured in flux. Eleven subjects with RLS/WED underwent 2 weeks of 14-minute intermittent WBV and a 2-week sham treatment in randomized order. Pre and post intervention RLS symptom severity were compared. Baseline SBF was compared between subjects with RLS/WED and an age- and sex-matched control group. A crossover design (aim 1) and a matched case-control design and repeated measures design (aim 2) were used. The data analyses consisted of 2-sample and paired t-tests; where applicable we used a standard crossover design adjustment. WBV did significantly decrease symptoms associated with RLS/WED compared to baseline data and compared to sham treatment. The baseline flux was significantly lower in RLS/WED subjects than matched controls, but this deficit was negated with WBV. There was no increase in resting SBF over the 2 weeks of treatment. Subjects with RLS/WED have decreased SBF but are able to increase flux to the same level as normal subjects with WBV. A 2-week intervention with WBV decreases symptoms associated with RLS/WED, but this does not seem to be related to an increase in resting SBF.

Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin

Calcitonin gene related peptide (CGRP) and substance P (SP) are neuropeptides that are simultaneously released from nociceptive C-fibers. CGRP is a potent vasodilator, inducing a long-lasting increase in superficial skin blood flow, whereas SP induces only a brief vasodilation but a significant plasma extravasation. CGRP and SP may play important roles in the pathophysiology of various pain states but little is known about their interaction.Different concentrations of SP (ranging from 10−5M to 10−9M) were applied to the volar forearm of 24 healthy subjects via dermal microdialysis. SP was applied either alone or in combination with CGRP10−9M and CGRP 10−6M.As expected, SP induced a transient increase in skin blood flow that decayed shortly after application. This transient blood flow peak was blunted with co-application of CGRP 10−9M and inhibited with co-application of CGRP10−6M. SP alone induced plasma protein extravasation (PPE). However, when CGRP10−6M was added, the PPE significantly increased.Our results demonstrate a complex interaction of the neuropeptides CGRP and SP. CGRP10−6M prevented SP-induced early vasodilation but augmented SP-induced PPE. These interactions might explain why vascular symptoms in chronic pain can differ strikingly between individuals.

Cardiovascular adaptations supporting human exercise-heat acclimation.

This review examines the cardiovascular adaptations along with total body water and plasma volume adjustments that occur in parallel with improved heat loss responses during exercise-heat acclimation. The cardiovascular system is well recognized as an important contributor to exercise-heat acclimation that acts to minimize physiological strain, reduce the risk of serious heat illness and better sustain exercise capacity. The upright posture adopted by humans during most physical activities and the large skin surface area contribute to the circulatory and blood pressure regulation challenge of simultaneously supporting skeletal muscle blood flow and dissipating heat via increased skin blood flow and sweat secretion during exercise-heat stress. Although it was traditionally held that cardiac output increased during exercise-heat stress to primarily support elevated skin blood flow requirements, recent evidence suggests that temperature-sensitive mechanisms may also mediate an elevation in skeletal muscle blood flow. The cardiovascular adaptations supporting this challenge include an increase in total body water, plasma volume expansion, better sustainment and/or elevation of stroke volume, reduction in heart rate, improvement in ventricular filling and myocardial efficiency, and enhanced skin blood flow and sweating responses. The magnitude of these adaptations is variable and dependent on several factors such as exercise intensity, duration of exposure, frequency and total number of exposures, as well as the environmental conditions (i.e. dry or humid heat) in which acclimation occurs.

The effect of heating rate on the cutaneous vasomotion responses of forearm and leg skin in humans

We examined skin blood flow (SkBF) and vasomotion in the forearm and leg using laser-Doppler fluxmetry (LDF) and spectral analysis to investigate endothelial, sympathetic, and myogenic activities in response to slow (0.1°C·10s−1) and fast (0.5°C·10s−1) local heating. At 33°C (thermoneutral) endothelial activity was higher in the legs than the forearms (P≤0.02). Fast-heating increased SkBF more than slow heating (P=0.037 forearm; P=0.002 leg). At onset of 42°C, endothelial (P=0.043 forearm; P=0.48 leg) activity increased in both regions during the fast-heating protocol. Following prolonged heating (42°C) endothelial activity was higher in both the forearm (P=0.002) and leg (P<0.001) following fast-heating. These results confirm regional differences in the response to local heating and suggest that the greater increase in SkBF in response to fast local heating is initially due to increased endothelial and sympathetic activity. Furthermore, with sustained local skin heating, greater vasodilatation was observed with fast heating compared to slow heating. These data indicate that this difference is due to greater endothelial activity following fast heating compared to slow heating, suggesting that the rate of skin heating may alter the mechanisms contributing to cutaneous vasodilatation.

Impairments in central cardiovascular function contribute to attenuated reflex vasodilation in aged skin.

During supine passive heating, increases in skin blood flow (SkBF) and cardiac output (Qc) are both blunted in older adults. The aim here was to determine the effect of acutely correcting the peripheral vasodilatory capacity of aged skin on the integrated cardiovascular responses to passive heating. A secondary aim was to examine the SkBF-Qc relation during hyperthermia in the presence (upright posture) and absence (dynamic exercise) of challenges to central venous pressure. We hypothesized that greater increases in SkBF would be accompanied by greater increases in Qc. Eleven healthy older adults (69 ± 3 yr) underwent supine passive heating (0.8°C rise in core temperature; water-perfused suit) after ingesting sapropterin (BH4, a nitric oxide synthase cofactor; 10 mg/kg) or placebo (randomized double-blind crossover design). Twelve young (24 ± 1 yr) subjects served as a comparison group. SkBF (laser-Doppler flowmetry) and Qc (open-circuit acetylene wash-in) were measured during supine heating, heating + upright posture, and heating + dynamic exercise. Throughout supine and upright heating, sapropterin fully restored the SkBF response of older adults to that of young adults but Qc remained blunted. During heat + upright posture, SkBF failed to decrease in untreated older subjects. There were no age- or treatment-related differences in SkBF-Qc during dynamic exercise. The principal finding of this study was that the blunted Qc response to passive heat stress is directly related to age as opposed to the blunted peripheral vasodilatory capacity of aged skin. Furthermore, peripheral impairments to SkBF in the aged may contribute to inapposite responses during challenges to central venous pressure during hyperthermia.

The effect of local repeated passive heating and handgrip exercise on reflex cutaneous vascular and sudomotor responses to whole-body heat stress

Enhancements in local cutaneous microvascular function are dependent upon elevations in both skin blood flow and temperature with repeated episodes of shear stress a key mechanism [1,2]. The mechanisms cause chronic sudomotor adaptations are not entirely clear however. Acute alterations in local cutaneous blood flow and temperature independently modify local sweat rate [3], possibly via variations in shear stress affecting endothelial nitric oxide release, suggesting that changes in skin blood flow and/or temperature may modulate sudomotor adaptations. It is also unclear as to the effects of localised thermal/hemodynamic interventions on neural cutaneous vascular and sudomotor responses. The aim of this study was to therefore compare the effects of repeated local forearm passive heating (that increases skin temperature and skin blood flow) and local handgrip exercise (that increases skin blood flow only) on sudomotor responses to whole-body heat stress.

Effect of acute systemic hypoxia on human cutaneous microcirculation and endothelial, sympathetic and myogenic activity

The regulation of cutaneous vascular tone impacts vascular vasomotion and blood volume distribution as a challenge to hypoxia, but the regulatory mechanisms yet remain poorly understood. A skin has a very compliant circulation, an increase in skin blood flow results in large peripheral displacement of blood volume, which could be controlled by local and systemic regulatory factors. The aim of this study was to determine the acute systemic hypoxia influence on blood flow in skin, local regulatory mechanism fluctuations and changes of systemic hemodynamic parameters. Healthy subjects (n=11; 24.9±3.7years old) participated in this study and procedures were performed in siting position. After 20min of acclimatization 15min of basal resting period in normoxia (pO2=21%) was recorded, followed by 20min in acute systemic hypoxia (pO2=12%), and after 15min of recovery period in normoxia (pO2=21%). HRV was used to evaluate autonomic nervous system activity to heart from systemic hemodynamic parameters which continuously evaluated cardiac output, total peripheral resistance and mean arterial blood pressure. Regional blood flow was evaluated by venous occlusion plethysmography and skin blood flow by laser-Doppler flowmetry. To evaluate local factor influences to cutaneous circulation wavelet analysis was used; fluctuations in the frequency intervals of 0.0095–0.021, 0.021–0.052, and 0.052–0.145Hz correspondingly represent endothelial, sympathetic, and myogenic activities. Our results from HRV data suggest that acute systemic hypoxia causes statistically significant increase of sympathetic (LF/HF; N1=0.46±0.25 vs. H=0.67±0.36; P=0.027) and decrease of parasympathetic (RMSSD; 80.0±43.1 vs. H=69.9±40.4, ms; P=0.009) outflow to heart. Acute hypoxia causes statistically significant increase of heart rate (RR interval; N1=960.3±174.5 vs. H=864.7±134.6, ms; P=0.001) and cardiac output (CO; N1=5.4 (5.2; 7.9) vs. H=6.7±1.4, l/min; P=0.020). Regional blood flow and vascular conductance were not changed during acute systemic hypoxia, but forearm skin blood flow (skin blood flow; N1=39.7 (34.0; 53.2) vs. H=51.6±13.9, PU; P=0.002) increases however local regulatory factor activity was not changed by acute systemic hypoxia. Acute systemic hypoxia causes sympathetic stimulation to heart which results in increased heart rate and larger cardiac output which could be the reason of forearm skin blood flow increase in acute systemic hypoxia without impact of local regulatory factors.

Local and remote thermoregulatory changes affect NIRS measurement in forearm muscles.

Near infrared spectroscopy (NIRS) assessment in skeletal muscle is potentially affected by circulatory changes occurring in superficial tissues. The aim of this study was to separately assess the interference from skin microcirculation and large vein blood flow by investigating the effect of selective local and remote warming-induced vasodilation, respectively. Blood volume and oxygenation changes were investigated in the forearm muscles of healthy subjects in two experimental series (ES) during selective forearm (ES1, n=12) or hand warming (ES2, n=10). In ES1, the response to muscle contraction (10s, 70% MVC) and occlusion before and after warming was also investigated, while in ES2 two NIRS probes were expressly positioned over a visible vein and over a vein-free area. Local warming increased the modified Beer-Lambert (BL) blood volume indicator, tHb, by 5.3±3.6µmol/Lcm to an extent comparable to post-contraction hyperemia (6.8±2.9µmol/Lcm, p<0.01). Remote warming increased skin blood flow at the hand and tHb at both forearm sites (on average: 5.4±4.8µmol/Lcm, p<0.01). Conversely, indicators of blood volume and oxygenation, based on spatially resolved spectroscopy (SRS), were not affected by any of the warming stimuli. These results demonstrate for the first time that: (1) blood drained by superficial veins may affect BL measurement; (2) it is difficult to exclude veins from the measurement by simple visual inspection of the cutaneous surface; (3) SRS effectively rejects artifacts from superficial hemodynamic changes in both cutaneous microcirculation and large veins. These results bear implications to conditions in which thermoregulatory adjustments cannot be excluded.

The ubiquitous ATP molecule: could it be the elusive thermal mediator igniting skin perfusion and sweating in the heat-stressed human?

Skin blood flow and sweating are two key thermoregulatory responses that help regulate body temperature in heat-stressed human beings. Adjustments in skin blood flow and sweating in response to thermal stimuli are mediated by local and reflex neural mechanisms (Johnson et al. 2014). Local thermosensitive mechanisms are important, as the application of heating to a particular area of the skin results in a localized elevation of blood flow and sweating in the heated skin. However, the precise pathways underpinning heat loss responses to heat stress, particularly those involving ATP as a mediator signal, are not fully established or understood. Heat stress-induced hyperthermia is associated with increases in intravascular ATP and accompanied by vasodilatation of the human skin and deep limb tissue vasculatures (Pearson et al. 2011; Heinonen et al. 2011). This supports a mechanistic coupling between the rise in intravascular ATP and the concomitant increase in local perfusion (Kalsi & Gonzalez-Alonso, 2012). However, sympathetic cholinergic nerves, which are known to modulate heat loss responses, co-release ATP with acetylcholine. These sensory nerves are therefore potential sources of ATP in the dermal interstitium. This raises the possibility that ATP may act as a thermal mediator signal, involved in the regulation of vasomotor and sudomotor activity in conditions of hyperthermia. In support of this idea, intradermal administration of ATP has been shown to induce cutaneous vasodilatation in human beings in vivo (Wingo et al. 2010), but the downstream mediators and its effect on sweating have not been investigated. Mechanistically, ATP can bind to P2Y purinergic receptors located in the cutaneous vasculature, and the sweat gland, and trigger cutaneous vasodilatation and increase sweating via at least three pathways: (i) activation of nitric oxide synthase (NOS), (ii) activation of cyclooxygenase (COX) and/or (iii) via the action of the ATP degradation compound adenosine. In this issue of The Journal of Physiology, Fujii et al. (2015) report the findings from an outstanding series of integrative physiology studies in human beings. The authors systematically investigated the roles of NOS and COX in the cutaneous vascular and sweating responses to intradermal administration of ATP, as well as the contribution of adenosine to ATP-induced skin vasodilatation in vivo. A major finding was that intradermal ATP infusion at a rate of 120 and 1200 nmol min−1 causes significant cutaneous vasodilatation. Co-infusion of the NOS inhibitor Nω–nitro-l-arginine (l-NNA) blunted about one-fourth of the ATP-evoked vasodilator response, implicating NOS as a mediator. The study also excluded two other potential regulatory pathways; blockade of COX or adenosine with co-infusion of ketorolac or theophylline did not alter the vasodilator response to intradermal ATP infusion. Lastly, none of the study protocols increased sweating. These observations collectively advance the basic physiological understanding of the control of skin blood flow and sweating. By showing that part of the vasodilator response to intradermal ATP administration is mediated by NOS and by providing conclusive evidence that ATP does not directly increase sweating in vivo, these data suggest that skin blood flow and sweating are not regulated by the same thermal mediator signal. The physiological relevance of interstitial ATP on thermal hyperaemia was not addressed in the study of Fujii et al. (2015). ATP needs to accumulate in the dermal interstitium for this ubiquitous molecule to exert its cutaneous vasodilator effects directly by binding to interstitial purinergic receptors. However, recent evidence suggests that local heating does not result in an accumulation of ATP in the interstitial space of human skin, and thus such accumulation is not necessary for local thermal hyperaemia to occur (Gifford et al. 2012). This observation and the additional finding by Fujii and coworkers that the intradermal administration of ATP at low infusion rates (0.12–12 nmol min−1) does not increase skin blood flow indicate that under physiological conditions ATP-mediated cutaneous vasodilatation is more likely to occur via the activation of purinergic receptors residing in the vascular endothelium. Although further research is needed to establish the physiological relevance of intravascular versus interstitial ATP in thermoeffector activity, the timely investigation of Fujii et al. (2015) highlights the capacity of ATP to be the elusive thermal mediator igniting skin perfusion in heat-stressed human beings, but not the signal that increases sweating.

Augmented reflex cutaneous vasodilatation following short-term dietary nitrate supplementation in humans.

What is the central question of this study? Nitrate supplementation via beetroot juice has been shown to have several benefits in healthy humans, including reduced blood pressure and increased blood flow to exercising muscle. Whether nitrate supplementation can improve blood flow to the skin in heat-stressed humans has not been investigated. What is the main finding and its importance? Similar to previous studies, we found that nitrate supplementation reduces blood pressure. Nitrate supplementation increased vasodilatation in the skin of heat-stressed humans but did not directly increase skin blood flow. Nitrate supplementation has been shown to increase NO-dependent vasodilatation through both NO synthase (NOS)-dependent and NOS-independent pathways. We hypothesized that nitrate supplementation would augment reflex cutaneous active vasodilatation. Subjects were equipped with two microdialysis fibres on the forearm randomly assigned as control (Ringer solution) or NOS inhibition (20mm l-NAME). Whole-body heating was performed to raise core temperature by 0.8°C above baseline core temperature. Maximal cutaneous vasodilatation was achieved via 54mm sodium nitroprusside and local heating to 43°C. Skin blood flow (measured by laser-Doppler flowmetry) and blood pressure were measured. Cutaneous vascular conductance (CVC) was calculated as skin blood flow divided by mean arterial pressure (MAP) and expressed as a percentage of maximal CVC (%CVCmax ). Subjects underwent heat stress before and after nitrate supplementation (3days of beetroot juice; 5mm, 0.45g nitrates per day). During heat stress, MAP was reduced following nitrate supplementation compared with the control conditions (before 88±3mmHg versus after 78±2mmHg; P<0.05); however, resting MAP was not different between conditions (before 88±3mmHg versus after 83±2mmHg; P=0.117). Nitrate supplementation increased plateau CVC at control sites (before 67±2%CVCmax versus after 80±5%CVCmax ; P=0.01) but not at l-NAME-treated sites (before 45±4%CVCmax versus after 40±5%CVCmax ; P=0.617). There was no change in the calculated percentage of NOS-dependent vasodilatation before and after supplementation (before 59±4%versus after 64±6%; P=0.577). These data suggest that nitrate supplementation augments CVC and reduces MAP during heat stress.

Healthy Aging does not Alter Sympathetic Drive during Whole‐Body Passive Heating

Increased muscle sympathetic nerve activity (MSNA) during heat stress in young humans likely reflects the sympathetic drive responsible for the cardiovascular adjustments that facilitate an increase in skin blood flow. In contrast, cardiovascular adjustments during heat stress are attenuated in the aged, and could therefore be due to a lower sympathetic drive. We compared plasma epinephrine ([E]) and norepinephrine ([NE]), as well as MSNA in 11 young (Y: 28 ± 4 y) and 8 aged (A: 71 ± 5 y) subjects prior to and during passive heat stress. A cold pressor test (CPT) was superimposed upon heating to assess if a ceiling in MSNA was attained. Baseline MSNA burst frequency (15 ± 7 vs. 29 ± 4 bursts/min, p=0.01) and burst incidence (26 ± 13 vs. 46 ± 8 bursts/100 c.c., p&lt;0.01) were greater in the aged. Heat stress increased core temperature to a similar extent in both groups (Y: +1.2 ± 0.1 vs. A: +1.2 ± 0.1°C, p=0.99). Changes in plasma [E] (Y: +21 ± 38 vs. A: ‐2 ± 37 pg/mL, p=0.24) and [NE] (Y: +182 ± 127 vs. A: +113 ± 156 pg/mL, p=0.32) with heating did not differ between groups. MSNA burst frequency (47 ± 10 vs. 61 ± 16 bursts/min, p&lt;0.01) and burst incidence (48 ± 14 vs. 65 ± 12 bursts/100 c.c., p=0.01) remained greater in the aged during heating, although both increased similarly between groups (p&gt;0.1). The CPT further increased MSNA burst frequency (Y: +11 ± 11 vs. A: +8 ± 5 bursts/min) and burst incidence (Y: +9 ± 11 vs. A: +10 ± 9 bursts/100 c.c), to a similar extent between groups (p&gt;0.1). These data suggest that the aged do not have a lower sympathetic drive during whole‐body passive heat stress. Funded by NIH HL61388.

Effect of continuous vs pulsed iontophoresis of treprostinil on skin blood flow

IntroductionSystemic sclerosis (SSc) is a rare disease affecting digital microcirculation, leading to finger ulcers and in some cases to amputation. Prostacyclin analogues can be used intravenously but their therapeutic effect is counterbalanced by potentially serious vasodilatation-induced side effects. Iontophoresis of treprostinil could be a promising local therapeutic alternative for SSc-related digital ulcers. Iontophoretic drug delivery is complex, and whether continuous or periodic current should be used remains debated. The objective of the present work is to compare the effect of continuous vs pulsed iontophoresis of treprostinil in rats. Materials and methodsTreprostinil (0.64mM and 0.064mM) and NaCl were delivered by cathodal iontophoresis onto the hindquarters of anaesthetized rats. Three protocols delivering the same quantity of current were compared: one was continuous (100μA during 20min) and two were periodic (B: twenty 1-min cycles with 200μA during 30s followed by 30s Off; and C: twenty 1-min cycles with 600μA during 10s followed by 50s Off) (n=8 for each protocol with each concentration). Skin blood flow was quantified using laser Doppler imaging and skin resistance was calculated with Ohm’s law. ResultsAll protocols induced a significant increase in skin blood flow. At the lower concentration (0.064mM treprostinil) the pulsed 10/50 sequence significantly enhanced cutaneous blood flow (Table 1; Fig. 1B) compared to continuous iontophoresis or the 30/30 sequence. We noted that the pulsed iontophoresis of NaCl (10/50 sequence) induced a significant early increase in cutaneous blood flow in comparison with continuous iontophoresis. Skin resistance measures were negatively correlated with current intensity delivered. ConclusionIn conclusion, pulsed iontophoresis of treprostinil with a 10s/50s (On/Off) protocol at 600μA increases the efficacy of iontophoresis at 0.064mM but not at a tenfold higher concentration. Pulsed iontophoresis could be used to optimize treprostinil iontophoresis, to provide similar efficacy with decreased costs, and should now be tested on humans.

Distinct Effects of Blood Flow and Temperature on Cutaneous Microvascular Adaptation

We performed two experiments to determine whether cutaneous microvascular adaptations in response to repeated core temperature (Tc) elevation are mediated by increases in skin blood flow (SkBF) and/or skin temperature. Healthy subjects participated for 8 wk in thrice-weekly bouts of 30-min lower limb heating (40°C). In study 1, both forearms were "clamped" at basal skin temperature throughout each heating bout (n = 9). Study 2 involved identical lower limb heating, with the forearms under ambient conditions (unclamped, n = 10). In both studies, a cuff was inflated around one forearm during the heating bouts to assess the contribution of SkBF and temperature responses. We assessed forearm SkBF responses to both lower limb (systemic reflex) heating and to local heating of the forearm skin, pre- and postintervention. Acutely, lower limb heating increased Tc (study 1, 0.63°C ± 0.15°C; study 2, 0.69°C ± 0.19°C; P < 0.001) and forearm SkBF (study 1, 0.13 ± 0.03 vs 1.52 ± 0.51; study 2, 0.14 ± 0.01 vs 1.17 ± 0.38 cutaneous vascular conductance (CVC); P < 0.001), with skin responses significantly attenuated in the cuffed forearm (P < 0.01). SkBF responses to local heating decreased in study 1 (clamped forearms; week 0 vs week 8, 1.46 ± 0.52 vs 0.99 ± 0.44 CVC; P < 0.05), whereas increases occurred in study 2 (unclamped; week 0 vs week 8, 1.89 ± 0.57 vs 2.27 ± 0.52 CVC; P < 0.05). Cuff placement abolished local adaptations in both studies. Our results indicate that repeated increases in SkBF and skin temperature result in increased skin flux responses to local heating, whereas repeated increases in SkBF in the absence of change in skin temperature induced the opposite response. Repeated increases in Tc induce intrinsic microvascular changes, the nature of which are dependent upon both SkBF and skin temperature.

Heat waves, aging, and human cardiovascular health.

This brief review is based on a President's Lecture presented at the Annual Meeting of the American College of Sports Medicine in 2013. The purpose of this review was to assess the effects of climate change and consequent increases in environmental heat stress on the aging cardiovascular system. The earth's average global temperature is slowly but consistently increasing, and along with mean temperature changes come increases in heat wave frequency and severity. Extreme passive thermal stress resulting from prolonged elevations in ambient temperature and prolonged physical activity in hot environments creates a high demand on the left ventricle to pump blood to the skin to dissipate heat. Even healthy aging is accompanied by altered cardiovascular function, which limits the extent to which older individuals can maintain stroke volume, increase cardiac output, and increase skin blood flow when exposed to environmental extremes. In the elderly, the increased cardiovascular demand during heat waves is often fatal because of increased strain on an already compromised left ventricle. Not surprisingly, excess deaths during heat waves 1) occur predominantly in older individuals and 2) are overwhelmingly cardiovascular in origin. Increasing frequency and severity of heat waves coupled with a rapidly growing at-risk population dramatically increase the extent of future untoward health outcomes.

Tissue oxygen saturation during hyperthermic progressive central hypovolemia.

During normothermia, a reduction in near-infrared spectroscopy (NIRS)-derived tissue oxygen saturation (So2) is an indicator of central hypovolemia. Hyperthermia increases skin blood flow and reduces tolerance to central hypovolemia, both of which may alter the interpretation of tissue So2 during central hypovolemia. This study tested the hypothesis that maximal reductions in tissue So2 would be similar throughout normothermic and hyperthermic central hypovolemia to presyncope. Ten healthy males (means ± SD; 32 ± 5 yr) underwent central hypovolemia via progressive lower-body negative pressure (LBNP) to presyncope during normothermia (skin temperature ≈34°C) and hyperthermia (+1.2 ± 0.1°C increase in internal temperature via a water-perfused suit, skin temperature ≈39°C). NIRS-derived forearm (flexor digitorum profundus) tissue So2 was measured throughout and analyzed as the absolute change from pre-LBNP. Hyperthermia reduced (P < 0.001) LBNP tolerance by 49 ± 33% (from 16.7 ± 7.9 to 7.2 ± 3.9 min). Pre-LBNP, tissue So2 was similar (P = 0.654) between normothermia (74 ± 5%) and hyperthermia (73 ± 7%). Tissue So2 decreased (P < 0.001) throughout LBNP, but the reduction from pre-LBNP to presyncope was greater during normothermia (-10 ± 6%) than during hyperthermia (-6 ± 5%; P = 0.041). Contrary to our hypothesis, these findings indicate that hyperthermia is associated with a smaller maximal reduction in tissue So2 during central hypovolemia to presyncope.

The interrelationship of research in the laboratory and the field to assess hydration status and determine mechanisms involved in water regulation during physical activity.

Changes in skin blood and sweating are the primary mechanisms for heat loss in humans. A hot, humid environment concomitant with dehydration limits the ability to increase skin blood flow for the purpose of transferring heat from the body core to skin surface and evaporate sweat to maintain core temperature within safe limits during exercise. Adequate hydration improves thermoregulation by maintaining blood volume to support skin blood flow and sweating. Humans rely on fluid intake to maintain total body water and blood volume, and have developed complex mechanisms to sense changes in the amount and composition of fluid in the body. This paper addresses the interrelationship of research in the laboratory and the field to assess hydration status involved in body water and temperature regulation during exercise. In the controlled setting of a research laboratory, investigators are able to investigate the contributions of volume and tonicity of fluid in the plasma to body water and temperature regulation during exercise and recovery. For example, laboratory studies have shown that tonicity in a rehydration beverage maintains the thirst mechanism (and stimulates drinking), and contributes to the ongoing stimulation of renal fluid retention hormones, ultimately leading to a more complete rehydration. Research in the field cannot control the environment precisely, but these studies provide a natural, ‘real-life’ setting to study fluid and temperature regulation during exercise. The conditions encountered in the field are closest to the environment during competition, and data collected in the field can have an immediate impact on performance and safety during exercise. There is an important synergy between these two methods of collecting data that support performance and protect athletes from harm during training and improve performance during competition.

Muscle oxygen saturation during hyperthermic central hypovolemia (1104.21)

During normothermia, a reduction in near infrared spectroscopy (NIRS) derived muscle oxygen saturation (SmO2) is an indicator of central hypovolemia. Hyperthermia reduces tolerance to central hypovolemia. This study tested the hypothesis that reductions in NIRS derived SmO2 would be similar throughout normothermic and hyperthermic central hypovolemia to pre‐syncope. Ten healthy males (32 ± 5 y) underwent central hypovolemia via progressive lower‐body negative pressure (LBNP) to pre‐syncope during normothermia and hyperthermia (+1.2 ± 0.1°C increase in internal temperature). NIRS derived SmO2 (Reflectance Medical Inc.) was measured throughout and analyzed as the absolute change from pre‐LBNP. Hyperthermia reduced (P&lt;0.001) LBNP tolerance by 38 ± 19%. Pre‐LBNP SmO2 was similar (P=0.654) between normothermia (74.1 ± 5.0%) and hyperthermia (72.6 ± 6.9%). SmO2 decreased (P&lt;0.001) throughout LBNP, but the absolute reduction from pre‐LBNP to pre‐syncope was greater (P=0.018) during normothermia (‐10.0 ± 5.7%) than during hyperthermia (‐5.7 ± 4.5%). These data indicate that hyperthermia influences the magnitude of the reduction in NIRS derived SmO2 during central hypovolemia to pre‐syncope. However, a potentially confounding influence of hyperthermia‐induced increases in skin blood flow affecting the NIRS derived SmO2 signal cannot be discounted.Grant Funding Source: DOD Grant 110475007