**3. Discussion**

*Basic and Clinical Understanding of Microcirculation*

increase.

is observed.

increased tone.

(p < 0.003) vasomotions.

neurogenic vasomotions (An), which can be regarded as an increase in the sympathetic adrenergic tone. Meanwhile, the basal tone of smooth muscle cells (Am) was

The tone-forming mechanisms were in a completely opposite state in the VP group. Relative to NT, there were no significant differences in the functional activity of the endothelial and neurogenic arteriolar tone regulation mechanisms, although there was a trend towards a vasomotion amplitude increase by these regulatory mechanisms. However, the basal tone of the smooth muscle cells in precapillary arterioles and capillary sphincters was significantly reduced (p < 0.05), which was indicated by the myogenic vasomotion amplitude (Am)

Thus, according to the functional state of the skin microcirculatory vessels, we obtained two completely opposite groups of patients with AH that initially seemed homogeneous. The differences between the groups were observed in all the six parameters analyzed: tissue perfusion (p < 0.002), amplitude of pulse (p < 0.002) and respiratory-associated (p < 0.000001) blood flow oscillations, amplitude of endothelial (p < 0.002), neurogenic (p < 0.003), and myogenic

From the data obtained it can be assumed that in AH patients without disruptions blood outflow from the capillary bed, hypertension is caused by an increase in the sympathetic adrenergic vascular tone regulation mechanism and by a vasomotor dysfunction of the microvascular endothelium. In patients with impaired blood outflow from the capillary bed associated with a decline in the myogenic tone of precapillary arterioles, an increase in the arterial blood inflow

The ABPM results were no less interesting. **Figure 5** shows significantly higher BP during both day and nighttime in the VP patients relative to VN, except for the nocturnal diastolic BP. A paradoxical situation arose – BP was higher in patients with a reduced resistive arteriolar tone than in patients with an

*The results of 24-h arterial blood pressure monitoring (ABPM). (А) Systolic BP (SBP). (B) Diastolic BP* 

unchanged and comparable to that in the control group (**Figure 4B**).

**142**

**Figure 5.**

*(DBP). (C) Mean BP (MBP).*

The pilot study of the functional state of the skin microvascular bed in essential arterial hypertension raised fundamental questions that require reflection and detailed consideration.

The first fundamental question is the validity of LDF in assessing the functional state of the resistive vascular bed in AH. On the one hand, there is no statistically significant correlation of BP with the functional activity of the tone-forming mechanisms in resistive arterioles. This can be explained by the absence of regulatory baroreflex mechanisms in the skin microvessels in contrast to microvessels in the striated muscle. On the other hand, the amplitude-frequency wavelet analysis of microcirculatory blood flow oscillations demonstrated that the functional state of the regulatory mechanisms in exchange microvessels may differ drastically in the initially homogeneous group of AH patients. This, in turn, not only has different hemodynamic and metabolic effects but quite evidently demands an individual approach to selecting antihypertensive therapy.

Let us consider the VN group in terms of the functional state of resistive arterioles. This group has a moderate decrease in the endothelial vasomotion amplitude with a trend towards significance (p = 0.065), indicating vasomotor dysfunction of the microvascular endothelium, which is consistent with the previously obtained results [36]. The group also exhibits a significant reduction in the neurogenic vasomotion amplitude (p < 0.002), which can be regarded as an increase in the sympathetic adrenergic tone. From the data obtained, it can be concluded that the functional state of resistive arterioles in AH patients with normal blood outflow from the capillary bed does not contradict Lang's neurogenic theory and the current ideas about the role of endothelial dysfunction in the AH pathogenesis. In such a functional state of the resistive arterioles, the prescription of drugs which lead to a tone decrease through various regulatory mechanisms can be considered quite justified.

Now let us consider the VP group, which raises many more questions. Based on the precapillary arteriole functional state, it can be concluded that there is a significant decrease in the basal tone of smooth muscle cells in arterioles and capillary sphincters. The insignificant (relative to NT) trend towards an amplitude increase (tone decline) of endothelial and neurogenic vasomotions can be explained in two ways: 1) changes in the regulatory systems themselves; 2) decreased smooth muscle cell sensitivity to the regulatory effects of the endothelium and the sympathetic adrenergic system. The hemodynamic consequences of the precapillary arteriolar tone are an increase in the arterial blood inflow (Ac), venular blood volume (Av), and as a result, tissue hyperperfusion, i.e. an increase in M.

Gryglewska et al. [37] also draw attention to a significant increase in the vasomotion amplitude in the neurogenic and myogenic activity range in patients with masked hypertension. The patients analyzed in that study were on average 10 years younger than our subjects. The data presented by the authors demonstrate that a neurogenic tone decline is observed against the background of an increased norepinephrine level. One possible cause for the increased plasma norepinephrine is the neurotransmitter leakage from the neuro-muscular synapses in microvessels in AH patients when the sympathetic nervous system activity is enhanced. This phenomenon is well-established for skeletal muscles [38, 39], but not for the skin microvessels which are not subject to baroreflex regulation [40]. The authors of the study suggest that the vasomotion amplitude increase in patients with masked hypertension is of a compensatory nature, aimed at meeting the metabolic needs of tissues when there is a reduced number of functioning capillaries, while the

increase in blood pressure is due to the influence of various hormones, proinflammatory cytokines, and other humoral substances possibly secreted by the visceral adipose tissue [37].

Similar results for the functional state of the resistive skin microvessels in AH patients were also obtained also in another study [41]. In an age-matched group, *Rossi* et al. observed a significant increase in tissue perfusion compared to normotensive subjects, associated with significantly higher vasomotion amplitudes within the range of the endothelial, neurogenic, respiratory (venular), and cardial blood flow modulation mechanisms. The authors explain the enhanced vasomotor function of the microvascular endothelium as a response to an increase in the shear stress at high BP values, and the higher vasomotion amplitude in the range of the neurogenic regulation mechanism as sympathetic nervous system activation. The authors consider the observed increase in the pulse oscillation amplitude a manifestation of a high BP level, and the rise in the respiratory-associated blood flow oscillation amplitude as a compensatory reaction aimed at extending the time for oxygen extraction by tissues under microvascular rarefication.

Hemodynamic changes at the MVB level entail significant metabolic changes. Of the three main metabolic mechanisms (diffusion, filtration-reabsorption, and vesicular), filtration-reabsorption depends directly on the hemodynamic parameters. This metabolic mechanism is described by the Starling equation and provides bidirectional transendothelial transport of water-soluble and low-molecular-weight substances due to the difference in the hydrostatic and colloid osmotic blood pressures. Enhanced arterial blood inflow (Ac) with impaired venular outflow (Av) in VP patients can lead to a substantial rise in hydrostatic pressure in the capillaries, which is observed in far from all AH patients during direct pressure measurement in the nail bed capillaries [42–44]. An increase in the capillary hydrostatic pressure leads to a shift in the filtration-reabsorption metabolic mechanism towards the predominance of filtration, with developing hyperhydration of the interstitial space and latent fluid retention in the tissues [45, 46]. The hyperhydration of the interstitial space increases the blood↔cell distance for nutrients and tissue metabolism products, leading to a disruption in the metabolic process rate.

Another very important issue is the choice of antihypertensive therapy in this group of patients. The choice of vasodilating drugs is highly dubious. An additional decline in the initially low resistive arteriolar tone can have a range of negative consequences, including orthostatic instability, syncope, peripheral edema, etc. The study by Makolkin et al. [47] is highly illustrative in this respect. The authors define several hemodynamic microcirculation types (normocirculatory, spastic, hyperemic, and congestive-stasical) and note the greatest effect of calcium antagonists in the spastic type, while these cause puffiness in the lower legs and feet, as well as hot flashes in the congestive-stasical type.

It can be speculated that patients in this group are poorly compliant with therapy due to low tolerability, or it is difficult to achieve the target BP. As Engholm et al. demonstrated in their study, in patients with a low systemic vascular resistance index (SVRI), additional administration of antihypertensive drugs from other groups (two-component therapy) significantly lowers BP without changing SVRI. There is also an insignificant trend towards an increase in the left atrial size with a decrease in the left ventricular stroke volume and cardiac index relative to patients with high SVRI [48]. Based on the functional state of the arteriolar and venular microvessels in the VP group, it can be assumed that in this case the prescription of drugs with venotonic and/or diuretic effects will be most justified.

The next important question is the reasons for such a substantial difference in the functional state of the skin microvessels, when all the parameters analyzed by LDF differ significantly. It can be assumed that this is due either to different

**145**

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension…*

etiological factors or to the pathological process duration. The early AH development stages are not marked by elevated levels of endothelin, a marker of vasomotor endothelial dysfunction [49]. We were not able to assess the pathological process duration in the analyzed groups, which is one among many weaknesses of this pilot study, but it can be assumed, based on the significant reduction in the microvascular endothelial vasomotor function, that the pathological process had been develop-

The role of the temporal factor in the detected functional differences is supported by studies of vasomotor function of microvessels in different AH models in laboratory animals. Boegehold et al. demonstrated that a high-salt diet for 6–7 weeks in healthy four-week old rats resulted in a significantly higher amplitude of vasomotions in the mesenteric arterioles with a diameter of 30 μm compared to the control group that did not received the salt load [50]. In another study in 10–12 week-old spontaneously hypertensive rats (SHR), Noble et al. not only observed a significant rise in the vasomotion amplitude in the spinal skeletal muscle arterioles with a diameter of <30 μm relative to those in normotensive animals, but also a significant increase in the diameter of precapillary arterioles (6–15 μm) and postcapillary venules (15–40 μm) [51]. In another study of the cerebral microvasculature in SHR, a significant increase in the vasomotion amplitude was demonstrated in micro- and larger (diameter 30–70 μm) vessels, where the smooth muscle layer is more pronounced and the neurogenic (sympathetic adrenergic) vascular tone regulation mechanism predominates [52]. The obtained experimental results in laboratory animals are quite consistent with the functional state of microvessels in the VP group, which may indirectly indicate the initial manifestations of the pathol-

This hypothesis is also supported by the high correlation of Av with MBP obtained in the combined NT + VP group (n = 63): day time – r = 0.66 (p < 0.0001); night time – r = 0.76 (p < 0.0001). This relationship indicates that the progression of disorders in the venular-venous vascular bed is accompanied by an increase of BP. It can be hypothesized that first the renin-angiotensin system is activated to maintain tissue homeostasis and compensate the filtration-reabsorption imbalance, leading to an increase in the resistive arteriolar tone, which in turn leads to a decrease in hydrostatic blood pressure in the capillaries. This regulatory mechanism restores the filtration-reabsorption metabolic balance but triggers a vicious circle which ultimately leads to structural microvascular changes. Based on this hypothesis, it can be suggested that the VP patients are at the early AH stage (functional impairment stage), and the VN patients have a longer course of the pathological process with the development of structural changes. It is extremely difficult to determine the AH course duration since many patients do not feel elevated BP. In this study, in 23 patients (37%) from both groups AH was diagnosed incidentally without any previous suspicion on their part about the existence of a pathology. Another important issue concerns the causes of disrupted blood outflow from the capillary bed, which may be due to several factors or their combination. One may be a disturbance in the functional state of the major veins which is observed both in laboratory animals [51] and in some AH patients and is expressed as a decrease in the venous wall elasticity with an elevation of their tone and the blood pressure in them [53–56]. Another cause may be an increase in the right atrial pres-

Another highly important issue concerns the BP level. What causes a higher BP level in VP patients relative to the VN group? The venular microvessels are generally believed to contribute not more than 8–9% of the PVR [59], although, as noted above, the contribution of the postcapillary section may be much higher [34]. But here another factor should be considered that significantly affects BP, i.e. the

*DOI: http://dx.doi.org/10.5772/intechopen.89852*

ing longer in the VN patients.

ogy in this group of patients.

sure, which is observed in some AH patients [57, 58].

#### *Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension… DOI: http://dx.doi.org/10.5772/intechopen.89852*

etiological factors or to the pathological process duration. The early AH development stages are not marked by elevated levels of endothelin, a marker of vasomotor endothelial dysfunction [49]. We were not able to assess the pathological process duration in the analyzed groups, which is one among many weaknesses of this pilot study, but it can be assumed, based on the significant reduction in the microvascular endothelial vasomotor function, that the pathological process had been developing longer in the VN patients.

The role of the temporal factor in the detected functional differences is supported by studies of vasomotor function of microvessels in different AH models in laboratory animals. Boegehold et al. demonstrated that a high-salt diet for 6–7 weeks in healthy four-week old rats resulted in a significantly higher amplitude of vasomotions in the mesenteric arterioles with a diameter of 30 μm compared to the control group that did not received the salt load [50]. In another study in 10–12 week-old spontaneously hypertensive rats (SHR), Noble et al. not only observed a significant rise in the vasomotion amplitude in the spinal skeletal muscle arterioles with a diameter of <30 μm relative to those in normotensive animals, but also a significant increase in the diameter of precapillary arterioles (6–15 μm) and postcapillary venules (15–40 μm) [51]. In another study of the cerebral microvasculature in SHR, a significant increase in the vasomotion amplitude was demonstrated in micro- and larger (diameter 30–70 μm) vessels, where the smooth muscle layer is more pronounced and the neurogenic (sympathetic adrenergic) vascular tone regulation mechanism predominates [52]. The obtained experimental results in laboratory animals are quite consistent with the functional state of microvessels in the VP group, which may indirectly indicate the initial manifestations of the pathology in this group of patients.

This hypothesis is also supported by the high correlation of Av with MBP obtained in the combined NT + VP group (n = 63): day time – r = 0.66 (p < 0.0001); night time – r = 0.76 (p < 0.0001). This relationship indicates that the progression of disorders in the venular-venous vascular bed is accompanied by an increase of BP. It can be hypothesized that first the renin-angiotensin system is activated to maintain tissue homeostasis and compensate the filtration-reabsorption imbalance, leading to an increase in the resistive arteriolar tone, which in turn leads to a decrease in hydrostatic blood pressure in the capillaries. This regulatory mechanism restores the filtration-reabsorption metabolic balance but triggers a vicious circle which ultimately leads to structural microvascular changes. Based on this hypothesis, it can be suggested that the VP patients are at the early AH stage (functional impairment stage), and the VN patients have a longer course of the pathological process with the development of structural changes. It is extremely difficult to determine the AH course duration since many patients do not feel elevated BP. In this study, in 23 patients (37%) from both groups AH was diagnosed incidentally without any previous suspicion on their part about the existence of a pathology.

Another important issue concerns the causes of disrupted blood outflow from the capillary bed, which may be due to several factors or their combination. One may be a disturbance in the functional state of the major veins which is observed both in laboratory animals [51] and in some AH patients and is expressed as a decrease in the venous wall elasticity with an elevation of their tone and the blood pressure in them [53–56]. Another cause may be an increase in the right atrial pressure, which is observed in some AH patients [57, 58].

Another highly important issue concerns the BP level. What causes a higher BP level in VP patients relative to the VN group? The venular microvessels are generally believed to contribute not more than 8–9% of the PVR [59], although, as noted above, the contribution of the postcapillary section may be much higher [34]. But here another factor should be considered that significantly affects BP, i.e. the

*Basic and Clinical Understanding of Microcirculation*

adipose tissue [37].

increase in blood pressure is due to the influence of various hormones, proinflammatory cytokines, and other humoral substances possibly secreted by the visceral

Similar results for the functional state of the resistive skin microvessels in AH patients were also obtained also in another study [41]. In an age-matched group, *Rossi* et al. observed a significant increase in tissue perfusion compared to normotensive subjects, associated with significantly higher vasomotion amplitudes within the range of the endothelial, neurogenic, respiratory (venular), and cardial blood flow modulation mechanisms. The authors explain the enhanced vasomotor function of the microvascular endothelium as a response to an increase in the shear stress at high BP values, and the higher vasomotion amplitude in the range of the neurogenic regulation mechanism as sympathetic nervous system activation. The authors consider the observed increase in the pulse oscillation amplitude a manifestation of a high BP level, and the rise in the respiratory-associated blood flow oscillation amplitude as a compensatory reaction aimed at extending the time for

Hemodynamic changes at the MVB level entail significant metabolic changes. Of the three main metabolic mechanisms (diffusion, filtration-reabsorption, and vesicular), filtration-reabsorption depends directly on the hemodynamic parameters. This metabolic mechanism is described by the Starling equation and provides bidirectional transendothelial transport of water-soluble and low-molecular-weight substances due to the difference in the hydrostatic and colloid osmotic blood pressures. Enhanced arterial blood inflow (Ac) with impaired venular outflow (Av) in VP patients can lead to a substantial rise in hydrostatic pressure in the capillaries, which is observed in far from all AH patients during direct pressure measurement in the nail bed capillaries [42–44]. An increase in the capillary hydrostatic pressure leads to a shift in the filtration-reabsorption metabolic mechanism towards the predominance of filtration, with developing hyperhydration of the interstitial space and latent fluid retention in the tissues [45, 46]. The hyperhydration of the interstitial space increases the blood↔cell distance for nutrients and tissue metabolism

Another very important issue is the choice of antihypertensive therapy in this group of patients. The choice of vasodilating drugs is highly dubious. An additional decline in the initially low resistive arteriolar tone can have a range of negative consequences, including orthostatic instability, syncope, peripheral edema, etc. The study by Makolkin et al. [47] is highly illustrative in this respect. The authors define several hemodynamic microcirculation types (normocirculatory, spastic, hyperemic, and congestive-stasical) and note the greatest effect of calcium antagonists in the spastic type, while these cause puffiness in the lower legs and feet, as well as hot

It can be speculated that patients in this group are poorly compliant with therapy due to low tolerability, or it is difficult to achieve the target BP. As Engholm et al. demonstrated in their study, in patients with a low systemic vascular resistance index (SVRI), additional administration of antihypertensive drugs from other groups (two-component therapy) significantly lowers BP without changing SVRI. There is also an insignificant trend towards an increase in the left atrial size with a decrease in the left ventricular stroke volume and cardiac index relative to patients with high SVRI [48]. Based on the functional state of the arteriolar and venular microvessels in the VP group, it can be assumed that in this case the prescription of drugs with venotonic and/or diuretic effects will be most justified. The next important question is the reasons for such a substantial difference in the functional state of the skin microvessels, when all the parameters analyzed by LDF differ significantly. It can be assumed that this is due either to different

oxygen extraction by tissues under microvascular rarefication.

products, leading to a disruption in the metabolic process rate.

flashes in the congestive-stasical type.

**144**

cardiac output. The cardiac output in AH patients may be elevated during venoconstriction [60]. Based on the significantly lower peripheral vascular resistance, the VP patients can be hypothesized to have a hyperkinetic circulation type, and their higher BP values are due to a combination of two factors – an increase in the cardiac output, as noted in other studies [48], and a disruption of the blood outflow from the capillary bed with an increase in PVR at the postcapillary (venular) level.

Regardless of the reasons for the hindered blood outflow from the capillary bed, the mechanism that increases the amplitude of myogenic vasomotions in the precapillary arterioles and capillary sphincters is baffling. Normally, in a closed cardiovascular system, an increase in the venous pressure results in a consecutive rise in the capillary and precapillary arteriolar pressure. The smooth muscle cells of the resistive microvessels respond to increased pressure and distension by contracting by the Ostroumov-Bayliss mechanism, which should lead to a rise in their tone with a decrease in the amplitude of myogenic vasomotions (Am). But in the VP group, the exact opposite effect is observed. How can we explain it?

It can be hypothesized that the precapillary arteriolar tone decline is of a compensatory nature, aimed at overcoming the raised resistance at the postcapillary level. The increase in the arterial blood inflow is aimed at overcoming the impaired venous outflow. But from the metabolic expediency point of view, this compensation mechanism is extremely unfavorable. This can be assumed to be a consequence of the functional features of the smooth muscle cells in VP patients. Falcone et al. established *in vivo* that an increase in venous pressure in the cremaster muscle of SHR caused a more pronounced constriction reaction of the 15–100 μm arterioles than in normotensive animals [61]. Another research group demonstrated on mesenteric arterioles (diameter 100–150 μm) *in vitro* that in SHR the smooth muscle cells (lacking sympathetic innervation) develop a significantly higher vasomotion amplitude in response to norepinephrine compared to normotensive animals [62].

The results of this pilot study suggest that the contribution of the venular MVB to PVR is more substantial, and the generally accepted vascular resistance scale requires adjustment. In previous studies on healthy normotensive volunteers it was demonstrated that the blood volume in the skin venular microvessels has a positive correlation with BP, and a negative correlation not only with the magnitude of nocturnal BP decline, but also with the dilation response of MVB during the heat test, the nociception system activation, and post-occlusive reactive hyperemia [63, 64]. MVB is anatomically located between the arterial and venous systems, and, as capillaries do not stretch, the disruptions in the outflow system naturally affect the inflow system to the exchange vessels with all the logical metabolic consequences. This state can be formulated simply as "no outflow – no inflow".

The venular MVB itself deserves special attention. What is the physiological underpinning of the significantly larger vascular volume in the venular MVB than on the arteriolar side? This is what Nature intended, and therefore there is a physiological reason. Unlike arterioles, which only regulate blood inflow to the capillaries, many important functions are performed at the venular level. One is that mast cells are located in the immediate vicinity of venules with a diameter of 40–80 μm. This protective system reacts to various chemical and biological noxious agents entering the systemic circulation and it is situated in the venular section of the MVB. Postcapillary venules provide the exchange of macromolecules and protein-bound substances in the bloodstream by vesicular transport. Recognition, immobilization, "unpacking" of transport molecules, and vesicle formation require some time and are facilitated by the hemodynamic conditions in the venular section of MVB, since it has the slowest blood flow in the entire cardiovascular system. The venular section occupies a strategic position and is the first to receive metabolic information.

**147**

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension…*

rine [65], dilation reactions to acetylcholine [66], adenosine [67], ATP [68], dilator prostanoids [69], and even to the metabolic stimulator 2,4-dinitrophenol [70]. In response to an increase in shear stress, venular endothelium produces NO leading to a corresponding dilation of the adjoining arteriole [71]. There is an opinion that the arteriolar NO level is determined by its venular concentration, whose basal level is maintained by the secretory activity of the venular endothelium [72]. The endothelium of the venous bed is also sensitive to the blood gas composition. Tkachenko demonstrated that with blood O2 saturation < 68% sympathetic stimulation leads to a contraction of the muscle veins (>100–150 μm), when O2 is in the range of 68–85%, the reaction can be both constriction and dilatation, but at saturation values of >85%, sympathetic

In the conducted studies it was discovered that any changes in venous MVB affect the functional state of the adjoining afferent arteriole and the effects are observed up to 12 mm from the stimulus applied. The following was revealed: constriction reactions of arterioles to intravenular administration of norepineph-

LDF is a relatively new technique for studying microcirculation in humans which is going through the stages of adoption, data accumulation, and interpretation of the obtained results. A review of the scientific literature over the past 20 years has identified only 143 studies of microcirculation in humans by LDF with wavelet analysis of blood flow oscillation. The total number of healthy subjects and patients with various organ and system diseases involved in the studies does not

The main aim of this pilot study was to evaluate the informativeness of LDF in assessing the functional state of the skin microvascular bed in patients with essential arterial hypertension. The study has many weaknesses, due to the retrospective data analysis and the inability to collect information on the central hemodynamic parameters and humoral status of the patients. Nevertheless, it can be concluded that the aim has been achieved. The obtained results are unexpected; however, they allow the microcirculatory blood flow problems in patients with AH to be viewed in

1.LDF is a very promising method to study the functional state of microcirculation in humans and can be useful for the selection of personalized antihyper-

2.The functional activity of the tone-forming mechanisms (endothelial, neurogenic, myogenic) of the resistive arterioles in the skin is not correlated with BP

3.AH patients can differ significantly in their functional status of resistive microvessels. One half of the patients have an increased arteriolar tone without hemodynamic disruptions in the venular MVB. The other half of the patients is a complete opposite, that is, they exhibit a decrease in arteriolar tone associated with disrupted blood outflow from the capillaries. These functional differences must be considered when selecting antihypertensive therapy. This may assist in increasing the effectiveness of therapy and patient compliance with

Several quite precise conclusions can be made based on the study:

*DOI: http://dx.doi.org/10.5772/intechopen.89852*

stimulation causes only venous dilation [73].

**4. Conclusion**

exceed 2600 [74].

an entirely new light.

tensive therapy.

the treatment.

according to ABPM data.

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension… DOI: http://dx.doi.org/10.5772/intechopen.89852*

In the conducted studies it was discovered that any changes in venous MVB affect the functional state of the adjoining afferent arteriole and the effects are observed up to 12 mm from the stimulus applied. The following was revealed: constriction reactions of arterioles to intravenular administration of norepinephrine [65], dilation reactions to acetylcholine [66], adenosine [67], ATP [68], dilator prostanoids [69], and even to the metabolic stimulator 2,4-dinitrophenol [70]. In response to an increase in shear stress, venular endothelium produces NO leading to a corresponding dilation of the adjoining arteriole [71]. There is an opinion that the arteriolar NO level is determined by its venular concentration, whose basal level is maintained by the secretory activity of the venular endothelium [72]. The endothelium of the venous bed is also sensitive to the blood gas composition. Tkachenko demonstrated that with blood O2 saturation < 68% sympathetic stimulation leads to a contraction of the muscle veins (>100–150 μm), when O2 is in the range of 68–85%, the reaction can be both constriction and dilatation, but at saturation values of >85%, sympathetic stimulation causes only venous dilation [73].
