Cutaneous Vasoconstrictor Response Research Articles

Cold-induced cutaneous vasoconstriction in humans: Function, dysfunction and the distinctly counterproductive.

What is the topic of this review? This review presents an update and synthesis of normal mechanisms of human cutaneous vasoconstriction in response to cold stress. It then discusses conditions in which cutaneous vasoconstrictor responses are excessive or insufficient and cases in which cold-induced vasoconstrictor responses become counter to maintaining thermal and haemodynamic homeostasis. What advances does it highlight? The review highlights our current understanding of the mechanisms that mediate alterations in cold-induced cutaneous vasoconstriction in pathology and environmental extremes, which has important clinical implications for preventing cold- and cardiovascular-related deaths. In humans, cold-induced peripheral vasoconstriction is an essential element of body temperature regulation. Given that the thermoregulatory system responds rapidly to changes in skin temperature, sympathetically mediated cutaneous vasoconstriction represents a crucial 'first line of defense' against excessive reduction in body temperature. Sympathetic noradrenergic vasoconstrictor nerves cause a rapid decrease in skin blood flow, thus increasing the insulative capacity of the skin and decreasing heat loss from the body. Small changes in the activity of these nerves are also responsible for the subtle changes in skin blood flow that occur with normal daily activities or minor changes in environmental temperature. With ageing, hypertension and other conditions, the cutaneous reflex vasoconstrictor response can become excessive or insufficient. Healthy older adults have impaired reflex vasoconstriction, which may result in an impaired ability to defend body temperature in some circumstances. Hypertension is associated with augmented vasoconstriction, which could have pathological implications for left ventricular afterload in individuals already at risk for cardiovascular events. Finally, in some cases, the reflex vasoconstrictor response becomes distinctly counterproductive to its own goals of maintaining cardiovascular and thermoregulatory homeostasis. Examples include Raynaud's phenomenon, in which exaggerated vasoconstriction can produce ischaemia in the periphery, and the cutaneous vasoconstrictor response to therapeutic body cooling in severe hyperthermia, which can limit the heat exchange necessary to prevent serious heat illness.

The contribution of noradrenergic nerves to the vasoconstrictor response during local cooling of leg and forearm skin in humans.

This study investigated the noradrenergic contribution during the cutaneous vasoconstrictor response to local cooling in the leg and forearm. On each limb, one site was perfused with Yoh/Prop to block the postsynaptic adrenoceptors and another with Lactated Ringer's (control) using microdialysis. Blood flow was measured by Laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF units divided by the mean arterial pressure. After baseline measures, skin was locally cooled to 24°C. Basal CVC was similar at all sites in the leg and forearm (all p > 0.1). During the first 10 min of local cooling, CVC was reduced in the leg (p < 0.005) and unchanged in the forearm control sites (p = 0.2). Yoh/Prop induced an increased CVC in the leg and forearm to a similar level (39.2 ± 11.5, and 41.3 ± 3.3%CVC, respectively; p < 0.35). Late during local cooling, the vasoconstriction was attenuated in the leg and forearm at Yoh/Prop (-38.2 ± 5.3 -37.1 ± 5.3%CVC, respectively; p = 0.5) compared to control sites (-69.1 ± 5.8 vs. -54.5 ± 6.4%CVC, respectively; p < 0.005). Noradrenergic contribution was greater in the leg than the forearm during the late vasoconstrictor response (p = 0.006). These data indicate that the leg skin can induce greater vasoconstriction than forearm during local cooling, possibly via higher noradrenergic sensitivity in the leg skin.

Role of cyclooxygenase in the vascular responses to extremity cooling in Caucasian and African males.

What is the central question of this study? Compared with Caucasians, African individuals are more susceptible to non-freezing cold injury and experience greater cutaneous vasoconstriction and cooler finger skin temperatures upon hand cooling. We investigated whether the enzyme cyclooxygenase is, in part, responsible for the exaggerated response to local cooling. What is the main finding and its importance? During local hand cooling, individuals of African descent experienced significantly lower finger skin blood flow and skin temperature compared with Caucasians irrespective of cyclooxygenase inhibition. These data suggest that in young African males the cyclooxygenase pathway appears not to be the primary reason for the increased susceptibility to non-freezing cold injury. Individuals of African descent (AFD) are more susceptible to non-freezing cold injury (NFCI) and experience an exaggerated cutaneous vasoconstrictor response to hand cooling compared with Caucasians (CAU). Using a placebo-controlled, cross-over design, this study tested the hypothesis that cyclooxygenase (COX) may, in part, be responsible for the exaggerated vasoconstrictor response to local cooling in AFD. Twelve AFD and 12 CAU young healthy men completed foot cooling and hand cooling (separately, in 8°C water for 30min) with spontaneous rewarming in 30°C air after placebo or aspirin (COX inhibition) treatment. Skin blood flow, expressed as cutaneous vascular conductance (as flux per millimetre of mercury), and skin temperature were measured throughout. Irrespective of COX inhibition, the responses to foot cooling, but not hand cooling, were similar between ethnicities. Specifically, during hand cooling after placebo, AFD experienced a lower minimal skin blood flow [mean (SD): 0.5 (0.1) versus 0.8 (0.2) fluxmmHg-1 , P<0.001] and a lower minimal finger skin temperature [9.5 (1.4) versus 10.7 (1.3)°C, P=0.039] compared with CAU. During spontaneous rewarming, average skin blood flow was also lower in AFD than in CAU [2.8 (1.6) versus 4.3 (1.0) fluxmmHg-1 , P<0.001]. These data provide further support that AFD experience an exaggerated response to hand cooling on reflection this appears to overstate findings; however, the results demonstrate that the COX pathway is not the primary reason for the exaggerated responses in AFD and increased susceptibility to NFCI.

Neurovascular mechanisms underlying augmented cold-induced reflex cutaneous vasoconstriction in human hypertension.

In hypertensive adults (HTN), cardiovascular risk increases disproportionately during environmental cold exposure. Despite ample evidence of dysregulated sympathetic control of the peripheral vasculature in hypertension, no studies have examined integrated neurovascular function during cold stress in HTN. The findings of the present study show that whole-body cold stress elicits greater increases in sympathetic outflow directed to the cutaneous vasculature and, correspondingly, greater reductions in skin blood flow in HTN. We further demonstrate an important role for non-adrenergic sympathetic co-transmitters in mediating the vasoconstrictor response to cold stress in hypertension. In the context of thermoregulation and the maintenance of core temperature, sympathetically-mediated control of the cutaneous vasculature is not only preserved, but also exaggerated in hypertension. Given the increasing prevalence of hypertension, clarifying the mechanistic underpinnings of hypertension-induced alterations in neurovascular function during cold exposure is clinically relevant. Despite ample evidence of dysregulated sympathetic control of the peripheral vasculature in hypertension, no studies have examined integrated neurovascular function during cold stress in hypertensive adults (HTN). We hypothesized that (i) whole-body cooling would elicit greater cutaneous vasoconstriction and greater increases in skin sympathetic nervous system activity (SSNA) in HTN (n=14; 56±2years) compared to age-matched normotensive adults (NTN; n=14; 55±2years) and (ii) augmented reflex vasoconstriction in HTN would be mediated by an increase in cutaneous vascular adrenergic sensitivity and a greater contribution of non-adrenergic sympathetic co-transmitters. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (water-perfused suit). Sympathetic adrenergic- and non-adrenergic-dependent contributions to reflex cutaneous vasoconstriction and vascular adrenergic sensitivity were assessed pharmacologically using intradermal microdialysis. Cooling elicited greater increases in SSNA (NTN: +64±13%baseline vs. HTN: +194±26%baseline ; P<0.01) and greater reductions in skin blood flow (NTN: -16±2%baseline vs. HTN: -28±3%baseline ; P<0.01) in HTN compared to NTN, reflecting an increased response range for sympathetic reflex control of cutaneous vasoconstriction in HTN. Norepinephrine dose-response curves showed no HTN-related difference in cutaneous adrenergic sensitivity (logEC50 ; NTN: -7.4±0.3log Mvs. HTN: -7.5±0.3log M; P=0.84); however, non-adrenergic sympathetic co-transmitters mediated a significant portion of the vasoconstrictor response to cold stress in HTN. Collectively, these findings indicate that hypertension increases the peripheral cutaneous vasoconstrictor response to cold via greater increases in skin sympathetic outflow coupled with an increased reliance on non-adrenergic neurotransmitters.

Desensitization of menthol-activated cold receptors in lower extremities during local cooling in young women with a cold constitution.

To test the hypothesis that topical menthol-induced reactivity of cold sensation and cutaneous vasoconstriction to local cooling is augmented in individuals with a cold constitution, we examined thermal sensation and cutaneous vasoconstrictor responses at menthol-treated and untreated sites in the legs during local skin cooling in young women complaining of chilliness (C group) and young women with no complaint as a normal control group (N group). During local skin cooling, the sensitivity to cold sensation was greater in the C group than in the N group. The application of menthol enhanced the cold sensation at a low temperature in the N group, but not in the C group. Cutaneous vasoconstrictor responses to local skin cooling were not altered by menthol treatment in either of the two groups. These findings suggest the desensitization of menthol-activated cold receptors in the legs of C group subjects, and a minor role of cold receptor activity in cutaneous vasoconstrictor response to local cooling.

Skin temperature measurements by infrared thermography during running exercise

The thermal interaction of human body and the environment during running activity is an important mechanism that may affect the athletic performance. Skin temperature plays the fundamental role of regulating the heat exchange by convection, radiation and evaporation. In this study, the skin temperature response to running exercise has been tested by infrared thermographic imaging, a highly reliable method for the real time, non-invasive monitoring of local cutaneous temperature over the body surface. Measurements performed for long-distance runners showed a fall in skin temperature during the initial stage of running exercise, regardless of the type of work (overground or treadmill) and environmental (outdoor or indoor) conditions. It is argued that this skin temperature decrease is associated with the cutaneous vasoconstrictor response to exercise. A continuous increase in load intensity (as occurs during an incremental treadmill exercise) may produce further reductions in skin temperature; conversely, a constant load running exercise is likely to promote the attainment of a relative minimum of skin temperature, followed by a gradual little rise over time related to thermoregulatory vasodilation.

The effects of ice vest pre-cooling on skin blood flow at rest and during exercise in the heat

Ice vest pre-cooling has been show to lower rectal tem- perature during intermittent exercise in hot conditions but only after 40 min of exercise [1]. The authors sug- gested that the ice vest may have initiated a strong local cutaneous vasoconstrictor response reducing skin blood flow [2] and thus the cooling potential, until increases in body temperature and skin blood flow occurred later in exercise. Therefore, the purpose of this study was to determine whether ice vest pre-cooling reduces skin blood flow during intermittent exercise in the heat com- pared to a no cooling control.

The cutaneous vasoconstrictor response in lower extremities during whole-body and local skin cooling in young women with a cold constitution

To clarify the characteristics of the thermal control of skin blood flow (SkBF) in individuals with a cold constitution, we examined the cutaneous vasoconstrictor responses in the calf and dorsal foot during whole-body and local skin cooling in young women complaining of chilliness (C group) and young women not suffering from it (N group). During whole-body skin cooling, the vasoconstrictor sensitivity in the dorsal foot, but not in the calf, was greater in the C group than in the N group. The C group also showed greater vasoconstrictor responses in the dorsal foot, but not in the calf, during local skin cooling and the iontophoretic application of norepinephrine. These findings suggest that the C group possesses a specific SkBF controlling system that is characterized by higher adrenergic sensitivity for greater cutaneous vasoconstriction in the distal portion of the lower extremities during cold exposure.

Do peripheral and/or central chemoreflexes influence skin blood flow in humans?

Voluntary apnea activates the central and peripheral chemoreceptors, leading to a rise in sympathetic nerve activity and limb vasoconstriction (i.e., brachial blood flow velocity and forearm cutaneous vascular conductance decrease to a similar extent). Whether peripheral and/or central chemoreceptors contribute to the cutaneous vasoconstrictor response remains unknown. We performed three separate experiments in healthy young men to test the following three hypotheses. First, inhibition of peripheral chemoreceptors with brief hyperoxia inhalation (100% O2) would attenuate the cutaneous vasoconstrictor response to voluntary apnea. Second, activation of the peripheral chemoreceptors with 5 min of hypoxia (10% O2, 90% N2) would augment the cutaneous vasoconstrictor response to voluntary apnea. Third, activation of the central chemoreceptors with 5 min of hypercapnia (7% CO2, 30% O2, 63% N2) would have no influence on cutaneous responses to voluntary apnea. Studies were performed in the supine posture with skin temperature maintained at thermoneutral levels. Beat‐by‐beat blood pressure, heart rate, brachial blood flow velocity, and cutaneous vascular conductance were measured and changes from baseline were compared between treatments. Relative to room air, hyperoxia attenuated the vasoconstrictor response to voluntary apnea in both muscle (−16 ± 10 vs. −40 ± 12%, P = 0.023) and skin (−14 ± 6 vs. −24 ± 5%, P = 0.033). Neither hypoxia nor hypercapnia had significant effects on cutaneous responses to apnea. These data indicate that skin blood flow is controlled by the peripheral chemoreceptors but not the central chemoreceptors.

Experimental investigation of non‐freezing cold‐induced injury: are young Asian males more susceptible than young white Caucasians and are cyclooxygenase products involved? (1106.5)

Prolonged or repeated exposure to cold conditions can induce NFCI; Afro‐Caribbeans are more susceptible than white Caucasians. We compared in Caucasian and Asian males (20‐22 years, n=6), responses evoked by 3 immersions of the right leg in water at 15°C for 10 min with 10‐min intervals, the left leg was ~horizontal. In Caucasians, cutaneous red cell flux in right foot (rRCF) fell from 12.8±2.4 to 11.6±1.3, 9.2±1.6* and 8.6±1.5PU in immersions 1, 2 and 3 with some recovery to11.3±2.4, 9.7±2.3* and 9.6±1.6* PU (*: P&lt;0.05 vs baseline). By contrast, in Asians, rRCF fell from 11.1±2.4 to as low as 7.0±0.9*, 6.3±0.8* and 5.8±0.7*PU, with no recovery: 6.8±0.8*, 6.6±0.8*, 6.8±0.7*PU. Caucasians showed no change in contralateral left RCF whereas in Asians, left RCF fell from 25.3±4.2 to 20.1±0.0.9, 20.4±2.8 and 20.5±0.7PU. After COX inhibition (aspirin; 600mg p.o), rRCF fell from 18.0±4.8 to 13.6±4.9*, 11.8±3.7* and 10.9±3.8* during 1st, 2nd and 3rd immersions in Caucasians, with no recovery: 13.5±4.0*, 13.2±4.7* and 11.7±4.0* PU. In Asians, rRCF fell from 7.7±0.9 to 5.9±0.7*, 5.6±0.6* and 5.8±0.6* PU, with no recovery: 5.8±0.9*, 5.6±0.7* and 5.6±0.7*PU. We suggest that young Asians show greater and more persistent local and reflex cutaneous vasoconstrictor responses to cool water immersion than Caucasians and so may be more vulnerable to NFCI; vasodilator COX products may limit cold‐induced vasoconstriction in Caucasians.

Blood pressure regulation in women – differences emerge when challenged by orthostasis

Blood pressure regulation in women – differences emerge when challenged by orthostasis

Elevated local skin temperature impairs cutaneous vasoconstrictor responses to a simulated haemorrhagic challenge while heat stressed

During a simulated haemorrhagic challenge, syncopal symptoms develop sooner when individuals are hyperthermic relative to normothermic. This is due, in part, to a large displacement of blood to the cutaneous circulation during hyperthermia, coupled with inadequate cutaneous vasoconstriction during the hypotensive challenge. The influence of local skin temperature on these cutaneous vasoconstrictor responses is unclear. This project tested the hypothesis that local skin temperature modulates cutaneous vasoconstriction during simulated haemorrhage in hyperthermic humans. Eight healthy participants (four men and four women; 32 ± 7 years old; 75.2 ± 10.8 kg) underwent lower-body negative pressure to presyncope while heat stressed via a water-perfused suit sufficiently to increase core temperature by 1.2 ± 0.2 °C. At forearm skin sites distal to the water-perfused suit, local skin temperature was either 35.2 ± 0.6 (mild heating) or 38.2 ± 0.2 °C (moderate heating) throughout heat stress and lower-body negative pressure, and remained at these temperatures until presyncope. The reduction in cutaneous vascular conductance during the final 90 s of lower-body negative pressure, relative to heat-stress baseline, was greatest at the mildly heated site (-10 ± 15% reduction) relative to the moderately heated site (-2 ± 12%; P = 0.05 for the magnitude of the reduction in cutaneous vascular conductance between sites), because vasoconstriction at the moderately heated site was either absent or negligible. In hyperthermic individuals, the extent of cutaneous vasoconstriction during a simulated haemorrhage can be modulated by local skin temperature. In situations where skin temperature is at least 38 °C, as is the case in soldiers operating in warm climatic conditions, a haemorrhagic insult is unlikely to be accompanied by cutaneous vasoconstriction.

Local skin temperature alters cutaneous vasoconstrictor responses to a simulated hemorrhagic challenge while heat stressed

Tolerance to simulated hemorrhage is reduced with hyperthermia, due in part to inadequate cutaneous vasoconstriction. It is unclear how elevated skin temperatures, as experienced by soldiers on active duty, influence cutaneous vasoconstriction during simulated hemorrhage. 8 healthy males (34 ± 9 yr, 80.2 ± 4.2 kg) underwent a simulated hemorrhagic challenge via lower body negative pressure (LBNP) to pre‐syncope while heat stressed sufficient to increase core (Tcore Δ1.2 ± 0.2°C) and mean skin temperatures (Tsk mean 38.2 ± 0.7°C). Local skin temperatures at three forearm sites were held at 35.2±0.6°C, 38.2±0.2°C and 41.3± 0.7°C throughout heat stress and LBNP. At pre‐syncope mean arterial pressure declined (74±6 to 53 ± 8 mmHg P &lt; 0.0001) while mean Tsk (38.2±0.7°C; P = 0.92) and local Tsk (35.1±0.8; 38.3±0.3 and 41.5±0.6°C; P &gt; 0.05) were unchanged relative to heat stress baseline (i.e., pre‐LBNP). The magnitude of reduction in cutaneous vascular conductance during the final 90 seconds of LBNP from heat stress baseline was influenced by local Tsk (8% at ~35°C; 3% at ~38°C and 2% at ~42°C; P &lt; 0.0001). In hyperthermic individuals the extent of cutaneous vasoconstriction during a simulated hemorrhage is dependent on skin temperature. In situations where a soldier's skin temperature exceeds 38°C, cutaneous vasoconstriction to a hemorrhagic challenge is likely negligible.NIH HL61388 and HL84072

Acute influence of oral vitamin C on the vasoconstrictor responses to local cooling and tyramine in human skin

It has been reported that orally ingesting vitamin C (Asc) enhanced the cutaneous vasoconstrictor response to local cooling (LC). In this study, we examined whether the increased vasoconstrictor response caused by oral Asc is due to the adrenergic system. The release of neurotransmitters from adrenergic nerves in forearm skin was blocked locally by iontophoresis of bretylium tosylate (BT). Skin blood flow (SkBF) was measured by laser‐Doppler flowmetry at BT‐treated and untreated sites. The skin sites were locally cooled from 34 to 24°C at −1°C/min and maintained at 24°C for 10 min before (Pre) and 1.5 h after (Post) oral Asc (2g single dose) supplementation. Cutaneous vascular conductance (CVC) was calculated as the ratio of SkBF to blood pressure and expressed relative to the baseline value before LC. Oral Asc enhanced (P&lt;0.05) the reductions in CVC at untreated sites but did not change the responses at BT‐treated sites during LC. To further examine whether adrenergically mediated vasoconstriction is enhanced by oral Asc, 0.1mM tyramine was administered using intradermal microdialysis in the forearm skin at 34°C in the Pre and Post periods. Oral Asc increased (P&lt;0.05) the tyramine‐induced reduction in CVC. These findings suggest that oral Asc acutely enhances the cutaneous vasoconstrictor responses to LC through the modification of adrenergic sympathetic mechanisms.

Oral vitamin C enhances the adrenergic vasoconstrictor response to local cooling in human skin

Local administration of ascorbic acid (Asc) at a supraphysiological concentration inhibits the cutaneous vasoconstrictor response to local cooling (LC). However, whether orally ingesting Asc inhibits the LC-induced vasoconstrictor response remains unknown. The purpose of the present study was to examine the acute influence of oral Asc on the adrenergic vasoconstrictor response to LC in human skin. In experiment 1, skin blood flow (SkBF) was measured by laser-Doppler flowmetry at three sites (forearm, calf, palm). The three skin sites were locally cooled from 34 to 24°C at -1°C/min and maintained at 24°C for 20 min before (Pre) and 1.5 h after (Post) oral Asc (2-g single dose) or placebo supplementation. Cutaneous vascular conductance (CVC) was calculated as the ratio of SkBF to blood pressure and expressed relative to the baseline value before LC. Oral Asc enhanced (P < 0.05) the reductions in CVC in the forearm (Pre, -50.3 ± 3.3%; Post, -57.8 ± 2.2%), calf (Pre, -52.6 ± 3.7%; Post, -66.1 ± 4.3%), and palm (Pre, -46.2 ± 6.2%; Post, -60.4 ± 5.6%) during LC. The placebo did not change the responses at any site. In experiment 2, to examine whether the increased vasoconstrictor response caused by oral Asc is due to the adrenergic system, the release of neurotransmitters from adrenergic nerves in forearm skin was blocked locally by iontophoresis of bretylium tosylate (BT). Oral Asc enhanced (P < 0.05) the reductions in CVC at untreated control sites but did not change the responses at BT-treated sites during LC. In experiment 3, to further examine whether adrenergically mediated vasoconstriction is enhanced by oral Asc, 0.1 mM tyramine was administered using intradermal microdialysis in the forearm skin at 34°C in the Pre and Post periods. Oral Asc increased (P < 0.05) the tyramine-induced reduction in CVC. These findings suggest that oral Asc acutely enhances the cutaneous vasoconstrictor responses to LC through the modification of adrenergic sympathetic mechanisms.

Age‐ and limb‐related differences in the vasoconstrictor response to limb dependency are not mediated by a sympathetic mechanism in humans

We tested the hypotheses that vasoconstrictor responses to limb dependency are: (i) greater in the leg than the arm, (ii) impaired with age and (iii) not sympathetically mediated. Vascular responses to limb dependency (i.e. lowering the limb from heart level to 30 cm below heart level) were determined in 17 young and 17 older adults. Indices of blood flow were obtained in the brachial and popliteal arteries (Doppler ultrasound) as well as in the cutaneous circulation (forearm and calf using laser-Doppler flowmetry). Vasoconstriction was quantified by calculating the indices of vascular resistance as height corrected mean arterial pressure/limb blood velocity or skin flux. A second group of subjects repeated the limb dependency trials after acute systemic sympathetic blockade. Limb dependency increased vascular resistance index in the brachial artery (∆59 ± 8%; P<0.05) and popliteal artery (∆99 ± 10%; P<0.05 for change in heart level and brachial vs. popliteal) of young and older adults (∆60 + 9% brachial and ∆61 ± 7% popliteal arteries; P<0.05 for change in heart level and response in popliteal young vs. older adults). In contrast, cutaneous vasoconstrictor responses to limb dependency were similar in the forearm (∆218 ± 29% and ∆200 ± 29% for young and older adults, respectively) and calf (∆257 ± 32% and ∆236 ± 29%; all P<0.05 from heart level) of young and older adults. Vasoconstrictor responses to limb dependency were not affected by sympathetic blockade in young or older adults. These findings indicate that age-, limb-, and tissue-related differences may exist in the vasoconstrictor response to limb dependency in healthy humans, which are not sympathetically mediated.

Limb-specific differences in the skin vascular responsiveness to adrenergic agonists

In this study, to test the hypothesis that adrenergic vasoconstrictor responses of the legs are greater compared with the arms in human skin, cutaneous vascular conductance (CVC) in the forearm and calf were compared during the infusion of adrenergic agonists in healthy young volunteers. Under normothermic conditions, norepinephrine (NE, α- and β-agonist, 1 × 10(-8) to 1 × 10(-2) M), phenylephrine (PHE, α(1)-agonist, 1 × 10(-8) to 1 × 10(-2) M), dexmedetomidine (DEX, α(2)-agonist, 1 × 10(-9) to 1 × 10(-4) M), and isoproterenol (ISO, β-agonist, 1 × 10(-8) to 1 × 10(-3) M) were administered by intradermal microdialysis. Skin blood flow (SkBF) was measured by laser-Doppler flowmetry, and the local temperature at SkBF-measuring sites was maintained at 34°C throughout the experiments. CVC was calculated as the ratio of SkBF to blood pressure and expressed relative to the baseline value before drug infusion. The dose of NE at the onset of vasoconstriction and the effective dose (ED(50)) resulting in 50% of the maximal vasoconstrictor response for NE were lower (P < 0.001) in the calf than forearm. The ED(50) for PHE and DEX was also lower (P < 0.05) in the calf than forearm. Increases in CVC in response to ISO were potentially smaller in the calf, but the statistical differences in the responses were dependent on the expressions of CVC. These findings suggest that the cutaneous vasoconstrictor responsiveness to exogenous NE is greater in the legs than in the arms due to a higher α(1)- and α(2)-adrenoceptor reactivity, while the β-adrenoceptor function plays a minor role in regional differences in adrenergic vasoconstriction in normothermic humans.

Local Heating as a Predilatation Method for Measurement of Vasoconstrictor Responses with Laser‐Doppler Flowmetry

Studying microvascular responses to iontophoresis of vasoconstricting drugs contributes to a better understanding of the regulatory mechanisms of cutaneous vessels, but measuring these responses with laser-Doppler flowmetry at basal blood flow conditions is technically challenging. This study aimed to investigate whether the measurement of cutaneous vasoconstrictor responses to noradrenaline (NA) and phenylephrine (PE), delivered by iontophoresis, is facilitated by predilatation of the microvascular bed using local heating. We used different drug delivery rates (100 s × 0.12 mA, 200 s × 0.06 mA, 300 s × 0.04 mA) to investigate whether predilatation affects the local drug dynamics by an increased removal of drugs from the skin. In a predilatated vascular bed, iontophoresis of NA and PE resulted in a significant decrease in perfusion from the thermal plateau (p < 0.001). The decrease was 25-33%, depending on drug delivery rate. In unheated skin, a significant vasoconstriction was observed (p < 0.001), with 17% and 14% decrease from baseline for NA and PE, respectively. These results indicate that predilatating the cutaneous vascular bed by local heating facilitates measurement of vasoconstriction with laser-Doppler flowmetry and does not seem to significantly affect the result by an increased removal of drugs from the skin.

Cutaneous vascular and sudomotor responses in human skin grafts

Each year millions of individuals sustain burns. Within the US 40,000-70,000 individuals are hospitalized for burn-related injuries, some of which are quite severe, requiring skin grafting. The grafting procedure disrupts neural and vascular connections between the host site and the graft, both of which are necessary for that region of skin to contribute to temperature regulation. With the use of relatively modern techniques such as laser-Doppler flowmetry and intradermal microdialysis, a wealth of information has become available regarding the consequences of skin grafting on heat dissipation and heat conservation mechanisms. The prevailing data suggest that cutaneous vasodilator capacity to an indirect heat stress (i.e., heating the individual but not the evaluated graft area) and a local heating stimulus (i.e., directly heating the graft area) is impaired in grafted skin. These impairments persist for ≥4 yr following the grafting procedures and are perhaps permanent. The capacity for grafted skin to vasodilate to an endothelial-dependent vasodilator is likewise impaired, whereas its capacity to vasodilate to an endothelial-independent vasodilator is generally preserved. Sweating responsiveness is minimal to nonexistent in grafted skin to both a whole body heat stress and local administration of the primary neurotransmitter responsible for stimulating sweat glands (i.e., acetylcholine). Likewise, there is no evidence that this absence of sweat gland responsiveness improves as the graft matures. In contrast to the heating stimuli, cutaneous vasoconstrictor responses to both indirect whole body cooling (i.e., exposing the individual to a cold stress but not at the evaluated graft area) and direct local cooling (i.e., directly cooling the graft area) are preserved in grafted skin as early as 5-9 mo postgrafting. If uninjured skin does not compensate for impaired heat dissipation of grafted skin, individuals having skin grafts encompassing significant fractions of their body surface area will be at a greater risk for a hyperthermic-related injury. Conversely, the prevailing data suggest that such individuals will not be at a greater risk of hypothermia upon exposure to cold environmental conditions.

Intradermal administration of ATP does not mitigate tyramine-stimulated vasoconstriction in human skin

Cutaneous vasodilation associated with whole-body heat stress occurs via withdrawal of adrenergic vasoconstriction and engagement of cholinergic "active" vasodilation, the latter of which attenuates cutaneous vasoconstrictor responsiveness. However, the precise neurotransmitter(s) responsible for this sympatholytic-like effect remain unknown. In skeletal muscle, ATP inhibits adrenergically mediated vasoconstriction. ATP also may be responsible for attenuating cutaneous vasoconstriction since it is co-released from cholinergic neurons. The effect of ATP on cutaneous vasoconstrictor responsiveness, however, has not been investigated. Accordingly, this study tested the hypothesis that ATP inhibits adrenergically mediated cutaneous vasoconstriction. To accomplish this objective, four microdialysis probes were inserted in dorsal forearm skin of 11 healthy individuals (mean +/- SD; 35 +/- 11 years). Local temperature at each site was clamped at 34 degrees C throughout the protocol. Skin blood flow was indexed by laser-Doppler flowmetry and was used to calculate cutaneous vascular conductance (CVC; laser-Doppler-derived flux/mean arterial pressure), which was normalized to peak CVC achieved with sodium nitroprusside infusion combined with local skin heating to approximately 42 degrees C. Two membranes were perfused with 30 mM ATP, while the other two membranes were flow matched via administration of 2.8 mM adenosine to serve as control sites. After achieving stable baselines, 1 x 10(-4) M tyramine was administered at all sites, while ATP and adenosine continued to be infused at their respective sites. ATP and adenosine infusion increased CVC from baseline by 35 +/- 26% CVC(peak) units and by 36 +/- 15% CVC(peak) units, respectively (P = 0.75). Tyramine decreased CVC similarly (by about one-third) at all sites (P < 0.001 for main effect and P = 0.32 for interaction). These findings indicate that unlike in skeletal muscle, ATP does not attenuate tyramine-stimulated vasoconstriction in human skin.