Skin Microhemodynamics and Mechanisms of Its Regulation in Type 2 Diabetes Mellitus.

The review presents modern ideas about peripheral microhemodynamics, approaches to the ana-lysis of skin blood flow oscillations and their diagnostic significance. Disorders of skin microhemodynamics in type 2 diabetes mellitus (DM) and the possibility of their interpretation from the standpoint of external and internal interactions between systems of skin blood flow regulation, based on a comparison of couplings in normal and pathological conditions, including models of pathologies on animals, are considered. The factors and mechanisms of vasomotor regulation, among them receptors and signaling events in endothelial and smooth muscle cells considered as models of microvessels are discussed. Attention was drawn to the disturbance of Ca2+-dependent regulation of coupling between vascular cells and NO-dependent regulation of vasodilation in diabetes mellitus. The main mechanisms of insulin resistance in type 2 DM are considered to be a defect in the number of insulin receptors and impaired signal transduction from the receptor to phosphatidylinositol-3-kinase and downstream targets. Reactive oxygen species plays an important role in vascular dysfunction in hyperglycemia. It is assumed that the considered molecular and cellular mechanisms of microhemodynamics regulation are involved in the formation of skin blood flow oscillations. Parameters of skin blood microcirculation can be used as diagnostic and prognostic markers for assessing the state of the body.

Anesthesia effects on the low frequency blood flow oscillations in mouse skin.

BACKGROUND: When laboratory animals are used one needs to anesthetize them before recording. However, the influence of anesthesia on animal blood flow oscillations has not been studied. The effects of two ways of anesthesia, zoletil-xylazine, and zoletil-nitrous oxide mixtures, on mouse skin perfusion using laser Doppler flowmetry (LDF) technique were studied. METHODS: BALB/c mice were used. LDF probe was placed on the ventral surface of the left hind paw. Spectral analysis of LDF signals was performed with continuous adaptive wavelet transform to identify and describe peripheral blood flow oscillations in mouse skin. RESULTS: Low-frequency oscillation interval boundaries (myogenic, neurogenic, and endothelial) for mice were shown to coincide with the boundaries determined for human and rats, that demonstrate their independence from the body size. Zoletil-xylazine anesthesia significantly decreased neurogenic and endothelial oscillation amplitudes by 29% and 50% respectively and increased the amplitude of cardiac oscillations by 23% compared to zoletyl-nitrous oxide anesthesia. There were no significant changes of the amplitudes of myogenic and respiratory oscillations with zoletil-nitrous oxide anesthesia compared to the zoletil-xylazine mixture. CONCLUSION: We suggest that the different influence of anesthesia modes on the amplitudes of skin blood flow oscillations is associated with sympathetic activity suppressed by zoletil-xylazine anesthesia.

Role of additive stochastic modulation of the heart activity in the formation of 0.1-Hz blood flow oscillations in the human cardiovascular system.

In the framework of our previous hypothesis about the participation of structural and hydrodynamic properties of the vascular bed in the formation of the 0.1-Hz component of blood flow oscillations in the human cardiovascular system and on the basis of the reduced hydrodynamic model, the role of additive stochastic perturbations of the operation of the single-chamber pump that simulates the heart was investigated. It was shown that aperiodic noise modulation of the rigidity of the walls of the pump or its valves generates low-frequency oscillations of pressure and blood flow velocity of arterial vascular bed with the maximum amplitude at a frequency close to 0.1 Hz.

[Effects of the Airway Obstruction on the Skin Microcirculation in Patients with Bronchial Asthma].

Background: Pulmonary hemodynamic disorders depend on the inflammatory phases and severity of the obstructive syndrome. However, the effect of asthma bronchial obstruction on the state of peripheral hemodynamics remains insufficiently known. Aims: To study the effects of airway obstruction on skin blood flow parameters and its regulatory systems in patients with persistent atopic bronchial asthma in the remission state. Materials and Methods: A comparative study of the skin peripheral blood flow in patients with bronchial asthma with severe airway obstruction (1st group) and without obstruction (2nd group) was conducted. 20 patients with confirmed diagnosis of atopic asthma of 50­74 years old participated in the study. All patients received basic therapy in a constant dosing of high doses of inhaled glucocorticosteroids/long-acting beta-2-agonists. The control group included 20 healthy volunteers without evidence of bronchial obstruction. The study lasted for 3 months. The forced expiratory volume in 1 s (FEV1) was used to evaluate the bronchial obstruction by spirometry technique. Skin blood perfusion changes were recorded by laser Doppler flowmetry at rest and in response to short-term local ischemia. Registered peripheral blood flow signals were examined using the amplitude temporal filtering in five frequency intervals to identify the functional features of the peripheral blood flow regulation systems. Results: Consistent two-fold decrease of the oscillation amplitudes was found in the neurogenic interval at rest (p=0.031), as well as in the myogenic (p=0.043; p=0.031) and endothelial intervals (p=0.037; p≤0.001) both at rest and during the postocclusive reactive hyperemia respectively in the 1st group of patients with bronchial obstruction (FEV1 <80%) compared with the control group. No significant changes were revealed for skin blood flow parameters in the 2nd patient group (without obstruction, FEV1 >80%) in comparison to control subjects. Conclusions: The presence of bronchial obstruction has a significant impact on the changes of the amplitudes of skin blood flow oscillations in patients with bronchial asthma in the myogenic, neurogenic and endothelial intervals.

[The significance of sympathovagal balance in the forming of respiration-dependent oscillations in cardiovascular system in human].

The effect of deep breathing controlled in both rate and amplitude on the heart rate variability (HRV) and respiration-dependent blood flow oscillations of forearm and finger-pad skin has been studied in 29 young healthy volunteers from 18 to 25 years old. To reveal the effect of the segments of the vegetative autonomic nervous system on the amplitudes of HRV and respiration-dependent oscillations of skin blood flow we estimated the parameters of the cardiovascular system into two groups of participants: with formally high and low sympathovagal balance values. The sympathovagal balance value was judged by the magnitude of LF/HF power ratio calculated for each participant using the spontaneous breathing rhythmogram. It was found what the participants with predominant parasympathetic tonus had statistically significant higher amplitudes of H R V and skin blood flow oscillations in the breathing rate less than 4 cycles per min than the subjects with predominant sympathetic tonus. In the forearm skin, where the density of sympathetic innervations is low comparatively to that in the finger skin, no statistically significant differences in the amplitude of respiratory skin blood flow oscillations was found between the two groups of participants.

[Physiological features of skin ageing in human].

The issue deals with the actual problem of gerontology, notably physiological features of human skin ageing. In the present review the authors have considered the kinds of ageing, central factors, affected on the ageing process (ultraviolet radiation and oxidation stress), as well as the research guidelines of the ageing changes in the skin structure and fuctions: study of mechanical properties, microcirculation, pH and skin thickness. The special attention has been payed to the methods of assessment of skin blood flow, and to results of investigations of age features of peripheral microhemodynamics. The laser Doppler flowmetry technique - one of the modern, noninvasive and extensively used methods for the assessmant of skin blood flow microcirculation system has been expanded in the review. The main results of the study of the ageing changes of skin blood perfusion using this method has been also presented.

[Age features of the dynamics of the oscillation amplitudes of the peripheral skin blood flow during the postocclusive reactive hyperemia].

The study of age-related changes of peripheral microhemodynamics was performed by laser Doppler flowmetry in 60 healthy volunteers. To determine the reaction of the microvascular system in response to short-term ischemia an occlusion test was used. To study the dynamics of the oscillation amplitudes of the peripheral blood flow the time-amplitude analysis on the basis of continuous adaptive wavelet filtration was used. It was found that the amplitudes of the oscillation in the range of heart rate in each age group reached its maxima with a delay after the occlusion stopping, whereas in the range of respiratory rhythm such delay was not observed. It is assumed that the formation ofhyperemic response to short-term ischemia occurs due to the preferential effect of arterio-arteriolar level, and the dynamics of the amplitudes in the range of respiratory rhythm reflects the devastation ofvenular level after occlusion stop. The observed age-related decreases of the maximum amplitudes in the range of myogenic, neurogenic and endothelial rhythms in response to shortterm ischemia demonstrate an age reduction limits of the peripheral blood flow regulation by related systems.

[Adaptive wavelet analysis of oscillations of the cutaneous peripheral blood flow in human].

The main principles of the method for the spectral timing analysis of the peripheral blood flow oscillations, obtained by laser Doppler flowmetry, have been presented. The method allows one to investigate the oscillations in a wide frequency range both in stationary and nonstationary conditions during the performance of functional tests. The potential of the method has been demonstrated in experiments with the reaction of the microvascular bed to the transcutaneous iontophoretic introduction of an acetylcholine chloride solution. The major advantage of the method as compared to the traditional wavelet analysis is a significant increase in the "effective" length of the signal analyzed. This allows a correct analysis of the low-frequency component of much shorter LDF recordings than those used in the traditional wavelet analysis.

[Age-dependent characteristics of the skin peripheral blood flow oscillations by nonlinear dynamics methods in humans].

Study of peripheral microhaemodynamics was carried out with laser Doppler flowmetry in healthy volunteers of different age groups. The ageing changes in the state of the skin peripheral blood flow, in the functioning of separate links and regulatory systems ofmicrovascular bed have been estimated in terms of relative entropy and fractal dimension values. The revealed significant age-dependent decrease of relative entropy values in the respiratory rhythm ranges, the neurogenic and myogenic activities yielded some evidence concerning the reduction of the microcirculation system chaotic changes within these frequency ranges during the ageing. The significant increase of fractal dimension values in the ranges of cardio-rhythm and the endothelial activity in the oldest group with the mean age of 77 years indicated that the structural complexity of the oscillations in these frequency ranges increased during ageing.

[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.

Lack of direct DNA damage in human blood leukocytes and lymphocytes after in vitro exposure to high power microwave pulses.

Currently, the potential genotoxicity of high power microwave pulses (HPMP) is not clear. Using the alkaline single cell gel electrophoresis assay, also known as the alkaline comet assay, we studied the effects of HPMP (8.8 GHz, 180 ns pulse width, peak power 65 kW, pulse repetition frequency 50 Hz) on DNA of human whole-blood leukocytes and isolated lymphocytes. The cell suspensions were exposed to HPMP for 40 min in a rectangular waveguide. The average SAR calculated from the temperature kinetics was about 1.6 kW/kg (peak SAR was about 300 MW/kg). The steady-state temperature rise in the 50 microl samples exposed to HPMP was 3.5 +/- 0.1 degrees C. In independent experiments, we did not find any statistically significant DNA damage manifested immediately after in vitro HPMP exposure of human blood leukocytes or lymphocytes or after HPMP exposure of leukocytes subsequently incubated at 37 degrees C for 30 min. Our results indicate that HPMP under the given exposure conditions did not induce DNA strand breaks, alkali-labile sites, and incomplete excision repair sites, which could be detected by the alkaline comet assay.

[Study of endothelium-dependent blood oscillations in the human skin microcirculatory bed].

Cutaneous microcirculation parameters were studied with laser Doppler flowmetry in healthy volunteers. To investigate endothelial-dependent peripheral blood flow oscillations the iontophoresis of 1% acetylcholine solution was carried out. To estimate the contribution of rhythmical components in blood flow signal the continuous wavelet-transform spectral analysis was used. To reveal correlation between microcirculation parameters under study the correlation analysis was used. The microcirculation index was shown to be the factor producing cross-correlation dependences. The only positive significant correlation between the blood flow oscillation amplitude in the range of endothelial activity normalized to mean microcirculation index at rest and maximal microcirculation index during the iontophoresis of acetylcholine was revealed.

[Aging features in functioning of skin microvascular bed in humans].

The state of skin microcirculation system has been studied in healthy volunteers aged from 20 to 77, using laser Doppler flowmetry. To reveal the reaction of microvascular bed in response to short-term ischemia, occlusive test has been carried out. During experiment the age-induced reduction of microcirculation index has been observed at rest. In response to stopping occlusion the 3.5--4-aliquot increase of microcirculation index has been revealed during reactive post-occlusive hyperemia in all age groups. The data obtained suggest maintenance of high reserve resources of skin microcirculation in ageing in response to ischemia.

[Estimation of age-related changes in the regulation of peripheral blood flow in humans].

The age-dependent features in the state of skin microvascular bed has been studied with laser Doppler flowmetry in healthy volunteers of different age groups. To reveal the reaction of skin blood flow in response to short-term ischemia, the occlusive test has been carried out. To estimate the contribution of rhythmic components to blood flow signal, continuous wavelet-transform spectral analysis was used. Age-dependent increase of pulse-wave amplitude and decrease of respiratory wave amplitude reflecting age-dependent changes in functioning of arteriolar and venular links of microvascular bed have been observed at rest. In response to short-term ischemia the age-dependent reduction of reserve resources has been revealed in functioning of arteriolar link of microvascular bed. The reduction of activity of myogenic, neurogenic and endothelial regulation systems have been shown at rest in ageing.