Phase synchronization of skin blood flow oscillations in humans under asymmetric local heating

The hypothesis is proposed that an external local stimulus may cause a change in the phase relationships of oscillations in the peripheral skin blood flow of contralateral extremities. To test this assumption, the wavelet phase coherence of skin blood flow oscillations of the left and right forearms of 18 healthy volunteers of both sexes at rest and in response to unilateral local heating was investigated. An area of the skin of the left forearm was exposed to heat and the native blood perfusion in an area of the skin of the right forearm was recorded simultaneously. It was shown that an asymmetric local change of skin perfusion led to a significant change in the phase relationships of the blood flow oscillations in all the analyzed frequency ranges. A significant reduction of phase synchronization of oscillations of skin blood flow in the range of endothelial, neurogenic, and myogenic activity, as well as in the range of respiratory rhythm was revealed. In contrast, in the range of the cardiac rhythm, a significant increase in phase synchronization of the oscillations of the blood flow of contralateral skin areas of the forearm was detected.     

Oscillatory processes in lymph microcirculation in the human skin

This study was the first to use laser Doppler flowmetry followed by wavelet analysis in order to estimate oscillations in lymph microcirculation in 30 subjects with (n = 13) or without (n = 17) edema of the distal part of the upper limb. Lymph flow in the human skin exhibited clear dominance of pacemaker phase oscillations in the frequency ranges of 0.021–0.042 and 0.016–0.035 Hz in the skin of the palm surface of the finger nail bone and in the skin of the forearm, respectively. Edema was associated with an increase in the peak frequencies and normalized maximum amplitudes (Al/Ml, where Al is the mean value of the maximum amplitude of phase oscillations, and Ml is the value of the averaged lymph flow expressed in perfusion units). Low-amplitude oscillations were recorded rarer in the myogenic, endothelial, and respiratory ranges. We did not find any cardiac pulse rhythm in the wavelet spectrum of the lymph flow. We did not find any interaction between the Al/Ml value and the skin temperature. In the group of subjects without edema, under physiological conditions only, we found a negative correlation between the Al/Ml value and the amplitudes of myogenous proper blood flow oscillations, which reflected the number of functional capillaries and activity of oxidative metabolism in the tissue. In the group with edema, we did not find any correlations between the indices of lymph flow and blood flow. The values of normalized amplitude and frequency of phase oscillations may be used as efficient diagnostic tools in the studies on lymph microcirculation.     

Assessment of microsphere technique for measurement of capillary blood flow in random skin flaps in pigs

In this technical paper, we reviewed the theory and methodology of the radioactive microsphere technique for determination of cardiac output and regional blood flow. Furthermore, we described two experiments conducted to assess this technique for measurement of capillary blood flow in skin-flap research. Our experimental data thus far indicated that the radioactive microsphere technique provided highly reproducible measurements for determination of capillary blood flow in 4 X 10 cm acute and delayed random skin flaps constructed in pigs. The advantages and disadvantages of this laboratory technique were also discussed.     

Evaluation of the use of an integration-type laser-Doppler flowmeter with a temperature-loading instrument for measuring skin blood flow in elderly subjects during cooling load: comparison with younger subjects

An integration-type laser-Doppler flowmeter, equipped with a temperature-load instrument, for measuring skin blood flow (ILD-T), and analytical parameters developed in a previous study were used to compare changes in the skin blood flow in the forehead and cheek in elderly subjects (in their 60s and 70s) with those in younger subjects (in their teens to 50s). Age-related differences in skin blood flow in the forehead and cheek in response to cooling were evaluated in 90 healthy women in their teens to 70s (mean age: 17.2 +/- 0.33 years for teenagers; 24.3 +/- 0.76 years for those aged 20-29 years; 34.8 +/- 1.12 years for those aged 30-39 years; 43.3 +/- 0.78 years for those aged 40-49 years; 53.8 +/- 1.13 years for those aged 50-59 years; 63.5 +/- 0.55 years for those aged 60-69 years; 72.2 +/- 0.70 years for those aged 70-79 years). The measurement was performed continuously for 5 min: for 1 min at a sensor temperature of 30 degrees C, for 2 min after the setting of the sensor temperature had been changed to 10 degrees C, and for 2 min after the temperature setting had been cancelled. The parameters analyzed were (1) skin temperature in a resting state before measurement ( T(rest)), (2) mean skin blood flow in 1 min at a sensor temperature of 30 degrees C ( F(30 degrees C)), (3) minimum skin blood flow at a sensor temperature of 10 degrees C ( F(min)), (4) slope of the blood flow plot during the period from the beginning of cooling at 10 degrees C to F(min) ( S(fall)), (5) time required for the sensor temperature to reach 10 degrees C (Delta t(s)), (6) maximum skin blood flow during the period from the end of cooling to the end of measurement ( F(max)), (7) slope of the blood flow plot during the period from F(min) to F(max) ( S(rise)), (8) rate of decrease of the skin blood flow during cooling: FDR = ( F(min)/ F(30 degrees C))x100, (9) recovery rate of the skin blood flow after the end of cooling: FRR = ( F(max)/ F(30 degrees C))x100. When correlations among the above nine parameters were evaluated by combining all age groups, significant correlations ( P < 0.01) were observed between F(30 degrees C) and F(min), F(30 degrees C) and F(max), F(30 degrees C) and S(fall), F(min) and F(max), and F(max) and S(rise) in the forehead. In the cheek, significant correlations ( P < 0.01) were observed in all these combinations except between F(max) and S(rise). When these analytical parameters were compared among the age groups, F(30 degrees C), T(rest), F(max), and S(rise) decreased significantly ( P < 0.02 for F(30 degrees C) and T(rest), P < 0.01 for F(max) and S(rise)) and S(fall) increased significantly ( P < 0.03) in the forehead with aging. However, no significant change with aging was observed in FDR, Delta t(s), F(min), and FRR. In the cheek, FDR increased significantly ( P < 0.03), and S(rise) decreased significantly ( P < 0.01) with aging. However, no significant change with aging was observed in F(30 degrees C), T(rest), F(max), S(fall), Delta t(s), F(min), and FRR. Thus, the decrease in the skin blood flow during cooling showed no marked quantitative change with age, but, with aging, the rate of this decrease was clearly reduced in the forehead. In the cheek, on the other hand, the skin blood flow decreased markedly with aging, but no clear change was observed in the rate of this decrease. By using ILD-T and examining various parameters obtained, the skin hemodynamics in the forehead and cheek during cooling from 30 degrees C to 10 degrees C could be analyzed, and differences in the hemodynamics between the forehead and cheek and between elderly and younger individuals were clarified. This instrument is expected to be clinically useful.     

Investigating high-amplitude oscillations in rat tail skin blood flow during core heating and cooling

In a separate paper, we describe high-amplitude oscillations in human skin blood flow (Q˙_sk). Using an open-loop model in rats, we independently modulated and clamped hypothalamic and skin temperatures. Central heating reliably induced these high-amplitude oscillations in tail Q˙_sk, which occurred at 0.41±0.03 Hz spanning 758.1±25.7 ms, and were comprised of high-amplitude peaks (496.8±87.6 AU) arising from a stable baseline (114.1±27.6 AU). Central cooling significantly reduced Q˙_sk, but not the amplitude, the frequency, width or baseline of the oscillations. These observations indicate that such high-amplitude oscillations are not primarily mediated via central thermal state. Instead, we believe these oscillations to be turned on by an elevated skin temperature.     

Modelling hand skin temperature in relation to body composition

Skin temperature is a challenging parameter to predict due to the complex interaction of physical and physiological variations. Previous studies concerning the correlation of regional physiological characteristics and body composition showed that obese people have higher hand skin temperature compared to the normal weight people. To predict hand skin temperature in a different environment, a two-node hand thermophysiological model was developed and validated with published experimental data. In addition, a sensitivity analysis was performed which showed that the variations in skin blood flow and blood temperature are most influential on hand skin temperature. The hand model was applied to simulate the hand skin temperature of the obese and normal weight subgroup in different ambient conditions. Higher skin blood flow and blood temperature were used in the simulation of obese people. The results showed a good agreement with experimental data from the literature, with the maximum difference of 0.31 °C. If the difference between blood flow and blood temperature of obese and normal weight people was not taken into account, the hand skin temperature of obese people was predicted with an average deviation of 1.42 °C. In conclusion, when modelling hand skin temperatures, it should be considered that regional skin temperature distribution differs in obese and normal weight people.     

The influence of the sympathetic innervation on the skin microvascular tone and blood flow oscillations

The influence of the sympathetic innervation on the tone of resistive vessels and blood flow oscillations was studied using laser Doppler flowmetry and skin thermography in 18 healthy subjects (before and after reflex cold and heat tests and local thermal testing), 42 patients with denervation syndromes caused by median nerve damage, and 10 patients with an acute stage of aseptic inflammation after radius fracture. The blood flow oscillations in the range of neurogenic sympathetic influences (0.02–0.052 Hz) supported by low-frequency sympathetic rhythms are an essential component of neurovascular interrelations. The importance of these oscillations is determined by their contribution to an increase in tissue perfusion owing to a decrease in the peripheral resistance and also by the leveling of drastic changes in blood flow and stabilization of microhemodynamics upon pronounced changes in the stationary tone. The high-and low-frequency (tonic and oscillatory, respectively) sympathetic rhythmic activities are expressed in two ways: (1) a synchronous increase or decrease in their amplitudes and (2) frequency dominance. The reactivity of the vessel smooth muscles is an important factor in maintaining the blood flow oscillations. Denervation decreases the oscillation amplitude in the neurogenic range. Under the conditions of local “inflammatory sympatholysis,” reflex tonic effects, rather than oscillatory ones, of the sympathetic impulses are mainly suppressed. An isolated evaluation of the blood flow oscillations in the neurogenic sympathetic range cannot be a measure of sympathetic activity. In studies on its functional state and evaluation of the neurogenic tone (NT) of resistive vessels, it is necessary to take into account the parameters of both stationary and oscillatory components of the NT.     

Dynamic autoregulation of cutaneous circulation: differential control in glabrous versus nonglabrous skin

The purpose of this project was to test the hypothesis that, independent of neural control, glabrous and nonglabrous cutaneous vasculature is capable of autoregulating blood flow. In 10 subjects, spectral and transfer function analyses of arterial pressure and skin blood flow (laser-Doppler flowmetry) from glabrous (palm) and nonglabrous (forearm) regions were performed under three conditions: baseline, ganglionic blockade via intravenous trimethaphan administration, and trimethaphan plus oscillatory lower body negative pressure (LBNP; -5 to -10 mmHg) from 0.05 to 0.07 Hz. Oscillatory LBNP was applied to regenerate mean arterial pressure variability that was abolished by ganglionic blockade. Ganglionic blockade was verified by an absence of a heart rate response to a Valsalva maneuver. Spectral power and transfer function gain between blood pressure and skin blood flow were calculated in this oscillatory frequency range (0.05-0.07 Hz). Within this frequency range, ganglionic blockade significantly decreased spectral power of blood flow in both the forearm and palm, whereas regeneration of arterial blood pressure oscillations significantly increased spectral power of forearm blood flow but not palm blood flow. During oscillatory LBNP, transfer function gain between blood pressure and skin blood flow was significantly elevated at the forearm (0.28 +/- 0.03 to 0.53 +/- 0.02 flux units/mmHg; P < 0.05) but was reduced at the palm (4.7 +/- 0.5 to 1.2 +/- 0.1 flux units/mmHg; P < 0.05). These data show that independent of neural control of blood flow, glabrous skin has the ability to buffer blood pressure oscillations and demonstrates a degree of dynamic autoregulation. Conversely, these data suggest that nonglabrous skin has diminished dynamic autoregulatory capabilities.     

Effects of blood flow,curved boundary and environmental conditions on temperature distribution in a two dimensional model of human skin and subcutaneous tissues

A mathematical model for the study of the effects of blood flow, metabolic heat production, various environmental conditions and the presence of a curved boundary on the temperature distribution (TD) in a two dimensional model of human skin and subcutaneous tissues (SST) is presented. Based on physiological properties, the interfaces between epidermis-dermis (IED) and dermis-subcutaneous tissues (IDS) have been considered to be irregular and the regions of these layers have been divided into 109 triangular elements of various sizes which are connected with each other by 70 nodes. The results computed from this thermobiological mathematical model, using Galerkin's finite element technique, have been exhibited graphically. The effects of various environmental conditions, blood flow and metabolic heat production are found to be nonuniform on TD at the nodes situated at the same depth in SST. This nonuniformity in TD almost disappears at the nodes situated in dermis nearest to IDS except for the two of the six combinations, considered in the present study, in which highest values of blood flow and metabolic heat production have been considered. The rate of fall of temperature with respect to thickness (towards the skin surface) is higher at the straight boundary (SB) than at the curved boundary (CB). The temperature increases with respect to width (from SB to CB) in epidermis and dermis but decreases in subcutaneous tissues. This increase or decrease of temperature is more pronounced at the nodes situated near to, or at CB. The trend of these temperature profiles in SST reflects the dependence of TD not only on the environmental conditions and biophysical variables but also on the geometry of SST.     

Detection of low- and high-frequency rhythms in the variability of skin sympathetic nerve activity

Spectral analysis of skin blood flow has demonstrated low-frequency (LF, 0.03-0.15 Hz) and high-frequency (HF, 0.15-0.40 Hz) oscillations, similar to oscillations in R-R interval, systolic pressure, and muscle sympathetic nerve activity (MSNA). It is not known whether the oscillatory profile of skin blood flow is secondary to oscillations in arterial pressure or to oscillations in skin sympathetic nerve activity (SSNA). MSNA and SSNA differ markedly with regard to control mechanisms and morphology. MSNA contains vasoconstrictor fibers directed to muscle vasculature, closely regulated by baroreceptors. SSNA contains both vasomotor and sudomotor fibers, differentially responding to arousals and thermal stimuli. Nevertheless, MSNA and SSNA share certain common characteristics. We tested the hypothesis that LF and HF oscillatory components are evident in SSNA, similar to the oscillatory components present in MSNA. We studied 18 healthy normal subjects and obtained sequential measurements of MSNA and SSNA from the peroneal nerve during supine rest. Measurements were also obtained of the electrocardiogram, beat-by-beat blood pressure (Finapres), and respiration. Spectral analysis showed LF and HF oscillations in MSNA, coherent with similar oscillations in both R-R interval and systolic pressure. The HF oscillation of MSNA was coherent with respiration. Similarly, LF and HF spectral components were evident in SSNA variability, coherent with corresponding variability components of R-R interval and systolic pressure. HF oscillations of SSNA were coherent with respiration. Thus our data suggest that these oscillations may be fundamental characteristics shared by MSNA and SSNA, possibly reflecting common central mechanisms regulating sympathetic outflows subserving different regions and functions.     

High-intensity static magnetic fields modulate skin microcirculation and temperature in vivo

We investigated the acute effect of static magnetic fields of up to 8 T on skin blood flow and body temperature in anesthetized rats. These variables were measured prior to, during, and following exposure to a magnetic field in a superconducting magnet with a horizontal bore. The dorsal skin was transversely incised for 1 cm to make a subcutaneous pocket. Probes of a laser Doppler flowmeter and a thermistor were inserted into the pocket and positioned at mid-dorsum to measure skin blood flow and temperature. Another thermistor probe was put into the rectum to monitor rectal temperature. After baseline measurement outside the magnet, the rat was inserted into the bore for 20 min so that mid-dorsum was exactly positioned at the center, where the magnetic field was nearly homogeneous. Post-exposure changes were then recorded for 20 min outside the bore. Sham-exposed animals were submitted to exactly the same conditions, except that the superconducting magnet was not energized. Skin blood flow and temperature decreased significantly during magnetic field exposure and recovered after removal of the animal from the magnet. The rectal temperature showed a tendency to decrease while the animal was in the magnet. The microcirculatory and thermal reactions in the present study were consistent and agreed with some of the predictions based on mathematical simulations and model experiments.     

Assessment of the changes in regulatory systems of human's skin blood flow during local heating

The mechanisms of thermal regulation of skin blood flow during local heating to 35, 40 and 45 'C have been studied by the method of laser Doppler flowmetry in healthy volunteers. To estimate the state of microvascular bed the continuous wavelet-transform spectral analysis has been used. The amplitudes of fluxmotions in the range of blood flow active modulation significantly increase during local heating to 35 degrees C. The amplitudes of blood flow oscillations in the ranges of cardiorhythm and respiratory rhythm increase during local heating to 40 degrees C. The high amplitude oscillations in the range of myogenic activity are maintained. The amplitude of oscillations in the range of endothelial activity distinctly decreases and the oscillations in the range of neurogenic activity are inhibited. Local heating to 45 degrees C results in a significant decreasing of the oscillation amplitudes in the range of myogenic activity, and the amplitudes of cardio- and respiratory spectral components amount to their peak values among the temperatures of local heating under study.     

Nonlinear relationship between level of blood flow and skin temperature for different dynamics of temperature change

We present a study of the relationship between blood flow and skin temperature under different dynamics of skin-temperature-change: locally induced thermal shock and well controlled, gradual change. First, we demonstrate memory phenomena for blood flow and skin temperature under both conditions. Secondly, we point out that the “hysteresis” loops obtained are dependent on initial conditions, indicating physiological response times of more than twenty minutes. We also show that under thermal shock the level of blood flow is preserved up to some characteristic temperature limit, independently of subject.     

Blood flow oscillations at a frequency of about 0.1 Hz in skin microvessels do not reflect the sympathetic regulation of their tone

Wavelet analysis of blood flow oscillations recorded with laser Doppler flowmetry in finger glabrous skin microvessels was carried out in 82 subjects with different variations in the syndromes of hand and foot sympathectomy and denervation. As distinct from the 0.02–0.046-Hz (about 0.03–0.04 Hz) blood flow oscillations in skin microvessels of sympathetic thermoregulatory origin, no relationship was found between the presence of 0.07–0.015 Hz (about 0.1 Hz) vasomotions in the wavelet spectrum and intactness of sympathetic innervation in the tissue region. The use of the myogenic band oscillation parameters, in particular, the amplitudes of vasomotions, for assessing the state of sympathetic thermoregulatory innervation determining the neurogenic tone of skin microvessels is not physiologically correct. The influence of local environmental factors on the vasomotion parameters confirms their local origin. The local perfusion pressure value significantly influenced the amplitude but not the frequency of vasomotions. The amplitude dominance of vasomotions was observed upon a decrease in perfusion pressure, whereas a marked increase in perfusion pressure or venous congestion resulted in a sharp depression of their amplitudes. Under the sympathectomy conditions, the oscillatory dynamic component of the arteriolar myogenic tone in the glabrous skin of the extremity acral zones is involved in the blood flow’s autoregulation. The presence of fine sensory fibers is necessary to carry out the dynamic autoregulation of the blood flow. Sensory nonmyelinated fibers and the trophic neuropeptides secreted by them not only initiate independent oscillations in the low-frequency (0.047–0.069 Hz) myogenic band, but also contribute to the normalized amplitudes of vasomotions being increased. At the same time, no appreciable influence of the sympathetic vasomotor activity and the corresponding influence of catecholamines on the amplitude and frequency of vasomotions was observed.     

A newly designed oscillating viscometer for blood viscosity measurements

A newly designed type of oscillating viscometer is described. The viscometer consists of either a tube or a rod oscillating at a resonance frequency with amplitudes in the micro- and nanometer range. A fluid flowing through the tube or surrounding the rod damps the torsional oscillations. The increase in the damping depends on the viscosity of the fluid and is used to determine viscosity. It was found that viscosity measurements are feasible during blood flow. This new type of viscometer may be useful to the study of biophysical properties of blood at the wall surface during flow and give new insights into blood flow. The device allows direct viscosity measurement on blood directly as it is drawn from the vein through the tube without any anticoagulant.     

Heat transfer analysis of skin during thermal therapy using thermal wave equation

Specifying exact geometry of vessel network and its effect on temperature distribution in living tissues is one of the most complicated problems of the bioheat field. In this paper, the effects of blood vessels on temperature distribution in a skin tissue subjected to various thermal therapy conditions are investigated. Present model consists of counter-current multilevel vessel network embedded in a three-dimensional triple-layered skin structure. Branching angles of vessels are calculated using the physiological principle of minimum work. Length and diameter ratios are specified using length doubling rule and Cube law, respectively. By solving continuity, momentum and energy equations for blood flow and Pennes and modified Pennes bioheat equations for the tissue, temperature distributions in the tissue are measured. Effects of considering modified Pennes bioheat equation are investigated, comprehensively. It is also observed that blood has an impressive role in temperature distribution of the tissue, especially at high temperatures. The effects of different parameters such as boundary conditions, relaxation time, thermal properties of skin, metabolism and pulse heat flux on temperature distribution are investigated. Tremendous effect of boundary condition type at the lower boundary is noted. It seems that neither insulation nor constant temperature at this boundary can completely describe the real physical phenomena. It is expected that real temperature at the lower levels is somewhat between two predicted values. The effect of temperature on the thermal properties of skin tissue is considered. It is shown that considering temperature dependent values for thermal conductivity is important in the temperature distribution estimation of skin tissue; however, the effect of temperature dependent values for specific heat capacity is negligible. It is seen that considering modified Pennes equation in processes with high heat flux during low times is significant.     

Forehead skin microcirculation during tilt table testing and lower body negative pressure

Noninvasive skin microcirculation measurements based on a new Near Infrared sensor technique (NIR/Fa. Silicon Sensor GmbH; Berlin) were embeded in a tilt table experiment for simulation of acute effects of weightlessness (HDT -6 degrees) and active standing with the Russian Tschibis-LBNP device. The phenomenon of orthostatic intolerance depends on complex interactions among functional characteristics of central and peripheral cardiovascular control. The purpose of this study was to assess the blood volume and flow motion changes as well as pulsatile spectral pattern during orthostatic and antiorthostatic stress.     

Dynamic oscillatory circuit of regulation of capillary hemodynamics

We used laser Doppler flowmetry with wavelet analysis of blood flow oscillations, computer capillaroscopy, and thermometry of the nail bed in 30 subjects to show an important role of the oscillatory circuit in the regulation of capillary hemodynamics, number of functioning capillaries, and linear and volumetric velocity of blood flow. The number of functioning capillaries is regulated by oscillations of myogenic and sensory peptidergic origin. The appearance of sensory oscillations, especially high-amplitude oscillations, is an adaptive neurotrophic mechanism that significantly increases the number of functioning capillaries and intensity of blood flow from arterioles to capillaries. The linear velocity of blood flow depends on both the tone of microvessels and changes in the dynamic component of blood pressure. Under conditions of skin hypoperfusion, the mean linear velocity of capillary blood flow may be inversely related to the extracapillary perfusion, including the amplitude of heart rate (A _h) and oscillations of the tone of precapillary sphincters, whereas under conditions of vasodilation and increased skin perfusion, it may be inversely related to the amplitude of arteriolar oscillations of endothelial or neurogenic sympathetic origin (A _maxe + n) and the shunting index. The A _h affects the linear velocity of blood flow in the arterial part of capillaries, whereas the A _maxe + n influences the same factor in the venous part. The contribution of oscillations to the regulation of the linear velocity varies depending on the perfusion and skin temperature. The resultant tone of distributing microvessels is determined by the competition between the stationary and oscillatory components. In addition to changes in the amplitude, the frequency of vasomotions may also be important. The regulatory importance of the oscillatory circuit is increased with a decrease in the skin blood flow.     

Hemodynamics and vascular sensitivity to circulating norepinephrine in normal skin and delayed and acute random skin flaps in the pig

Cutaneous circulation in 4 X 10 cm skin samples and delayed and acute random skin flaps constructed on the flanks of castrated Yorkshire pigs (13.3 +/- 0.7 kg; n = 12) were studied during intravenous infusion (0.5 ml per minute) of 5% dextrose solution (vehicle) and 5% dextrose containing norepinephrine (1 microgram/kg per minute). Total and capillary blood flow and A-V shunt flow were measured by the radioactive microsphere technique 6 hours after the raising of 4 X 10 cm single-pedicle acute and delayed random skin flaps using the technique and calculations published previously. Fluorescein dye test was also performed to assess vascular perfusion. It was observed that the capillary blood flow in the single-pedicle delayed skin flaps was similar to that in the normal skin, and the maintenance of this normal skin blood flow was not due to the closing of A-V shunt flow in the delayed skin flaps. Similarly, the significant (p less than 0.01) decrease in capillary blood flow and distal perfusion in the acute skin flaps compared with the delayed skin flaps was not due to the opening of A-V shunts in the acute skin flaps. There was no evidence to indicate that A-V shunt flow per se was the primary factor for the regulation of capillary blood flow in the acute and delayed skin flaps in the pig. Our data seemed to indicate that tissue ischemia in the distal portion of acute skin flaps was likely the result of vasoconstriction of the small random arteries which supplied blood to arterioles and A-V shunts, and locally released neurohumoral substances may play an important role in the pathogenesis of vascular resistance and ischemia in the acute skin flaps.