The role of superoxide anions in regulation of coronary vessel tone and myocardial contractile function in changed redox-state of the myocardium

The study relates to the character of tirone effect (chemical trap of superoxide--anions) on regulation of coronary vessel tone and myocardial contractile function in normal and changed cell redox-state of coronary and cardiac vessels. The experiments were performed in 64 female Wistar rats (180-320 g). The coronary blood flow and myocardial contractile junction were studied in isolated heart preparations. To determine the role of superoxide-anions in regulation of coronary vessel tone, tirone was added to the perfusion solution (4,5-dihydroxy-1,3-benzene disulfonic acid, 10 mm, Sigma USA). Preliminary injection of N-acetyl-L-cysteine evoked a 16 % increase, whereas injection of L-buthionine-(S,R)-sulfoximine reduced concentration of nonprotein thiol group in the myocardium and erythrocytes of experimental animals by 37%. The influence of superoxide anions on the cardiac vessel tone and myocardial contractile function was due to nitric monoxide participation the concentration of which increased in binding of superoxide anions and was directly dependent on concentration of sulfhydrilis groups in the cardiac cells. The oxygen active forms and cellular redox-state seem to play an important role in the regulation mechanisms of the coronary vessel tone and myocardial contractile function.     

Homogenization modeling for the mechanics of perfused myocardium

Altered coronary perfusion can change the apparent diastolic stiffness of ventricular myocardium--the ‘garden hose’ effect. Our recent findings showed that myocardial strains are reduced during ventricular filling, primarily along the directions transverse to the coronary microvessels. In this article, we review hypotheses and theoretical models regarding the role that regional wall stress plays in the mechanical interaction between myocardium and coronary circulation. Various mechanisms have been used to explain the effects of the tissue stress on coronary flow, as well as the effect of coronary dynamics on myocardial mechanics. Many models of coronary pressure-flow relations using lumped parameter circuit analogs. Poroelasticity and swelling theories have been used to model the mechanics of perfused muscle. Here, we describe a new mathematical model of the mechanics of perfused myocardium derived using homogenization theory. In this model, perfused myocardium is treated as a nonlinear anisotropic elastic solid embedded with cylindrical vessels of known distensibility. The solid compartment is incompressible but the vascular compartment may change volume according to a simple relation between vessel diameter and perfusion pressure. The work done by the perfusion pressure in changing vascular volume contributes to the macroscopic strain energy and hence affects the stress and stiffness of the composite. Conversely, the stress in the tissue affects microvessel diameter and volume, since tractions transverse to the vessel axis oppose the internal blood pressure. Finite element simulations of passive filling show good agreement of model with experimental results.     

Beating myocardium counteracts myogenic tone of coronary microvessels: involvement of ATP-sensitive potassium channels

Myogenic tone is intrinsic to vascular tissue and plays an important role in determining basal coronary resistance. However, the effect of the beating heart on myogenic tone is unknown. We investigated the effects of myocardium-derived vasoactive factors on the myogenic tone of coronary microvessels in the resting condition and during increased metabolism. Pressurized isolated coronary vessels (detector vessel, DV) of rabbits (n = 33, maximal inner diameter 201 +/- 8 microm) were gently placed on beating hearts of anesthetized dogs and observed with an intravital microscope equipped with a floating objective. To shut off the myocardium-derived vasoactive signals, we placed plastic film between DV and the heart. The intravascular pressure was changed from 120 to 60 cmH(2)O, and pressure-diameter curves were obtained with and without the contact of DV and the myocardium. The direct contact shifted the pressure-diameter curve upward (P < 0.05 vs. without contact), and myogenic tone was reduced by approximately 40%. When endothelium of DV was denuded, the shift persisted, but the degree of shift was reduced to 10% (P < 0.05 vs. with endothelium). The shift was abolished by glibenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker. A similar upward shift was induced by rapid pacing, but the shift was not blocked by glibenclamide. We conclude that the beating myocardium counteracts myogenic tone by releasing transferable vasoactive signals that affect the endothelium and the vascular smooth muscle, and that the signals are solely mediated by the activation of K(ATP) channels, unlike the rapid pacing-induced vasoactive factors.     

Biophysical Model of the Spatial Heterogeneity of Myocardial Flow

The blood flow in the myocardium has significant spatial heterogeneity. The objective of this study was to develop a biophysical model based on detailed anatomical data to determine the heterogeneity of regional myocardial flow during diastole. The model predictions were compared with experimental measurements in a diastolic porcine heart in the absence of vessel tone using nonradioactive fluorescent microsphere measurements. The results from the model and experimental measurements showed good agreement. The relative flow dispersion in the arrested, vasodilated heart was found to be 44% and 48% numerically and experimentally, respectively. Furthermore, the flow dispersion was found to have fractal characteristics with fractal dimensions (D) of 1.25 and 1.27 predicted by the model and validated by the experiments, respectively. This validated three-dimensional model of normal diastolic heart will play an important role in elucidating the spatial heterogeneity of coronary blood flow, and serve as a foundation for understanding the interplay between cardiac mechanics and coronary hemodynamics.     

Static magnetic fields alter arteriolar tone in vivo

This study was designed to directly quantify the effect of localized static magnetic field (SMF) exposure on the diameter of microvessels in adult rat skeletal muscle in vivo. Microvascular networks in the exteriorized rat spinotrapezius microvasculature were exposed to a localized, uniform 70 mT SMF for 15 min. Arteriolar vessel diameters were measured; and the extent of vessel contraction, microvascular tone, was calculated before exposure, immediately after exposure, and 15 and 30 min after removal of the field. A calculated value of high tone corresponds to vessels that are vasoconstricted and a calculated value of low tone refers to vessels that are vasodilated. Vessels with initial tone <15% showed an increasing trend in tone and, conversely, vessels with initial tone >15% showed a significant (P < 0.05) decrease in tone 15 and 30 min following application, respectively. Further classification of the data with regards to the initial vessel diameter demonstrated that vessels with initial diameters <30 microm and initial tone <15%, smaller diameter vessels that are initially vasodilated, showed significant (P < 0.05) increase in tone immediately, 15 and 30 min following SMF exposure. Additionally, <30 microm vessels with >15% initial tone, smaller diameter vessels that are initially vasoconstricted, demonstrated a significant (P < 0.05) decrease in tone 30 min after SMF exposure. Vessels with initial diameters >30 microm had no significant response to the SMF. These results imply that SMF exposure influences arteriolar diameters, and therefore microvascular tone, in a restorative fashion acting to normalize the tone to the median tone value of 15% following exposure. Because this response occurs primarily in the resistance arterioles, which significantly influence tissue perfusion, SMF application could be efficacious for the treatment of both ischemic and edematous tissue disorders involving compromised microvascular function.     

Effects of myocardial constraint on the passive mechanical behaviors of the coronary vessel wall

The large epicardial coronary arteries and veins span the surface of the heart and gradually penetrate into the myocardium. It has recently been shown that remodeling of the epicardial veins in response to pressure overload strongly depends on the degree of myocardial support. The nontethered regions of the vessel wall show significant intimal hyperplasia compared with the tethered regions. Our hypothesis is that such circumferentially nonuniform structural adaptation in the vessel wall is due to nonuniform wall stress and strain. Transmural stress and strain are significantly influenced by the support of the surrounding myocardial tissue, which significantly limits distension of the vessel. In this finite-element study, we modeled the nonuniform support by embedding the left anterior descending artery into the myocardium to different depths and analyzed deformation and strain in the vessel wall. Circumferential wall strain was much higher in the untethered than tethered region at physiological pressure. On the basis of the hypothesis that elevated wall strain is the stimulus for remodeling, the simulation results suggest that large epicardial coronary vessels have a greater tendency to become thicker in the absence of myocardial constraint. This study provides a mechanical basis for understanding the local growth and remodeling of vessels subjected to various degrees of surrounding tissue.     

Diameter-dependent axial prestretch of porcine coronary arteries and veins

The pressure-diameter relation (PDR) and the wall strain of coronary blood vessels have important implications for coronary blood flow and arthrosclerosis, respectively. Previous studies have shown that these mechanical quantities are significantly affected by the axial stretch of the vessels. The objective of this study was to measure the physiological axial stretch in the coronary vasculature; i.e., from left anterior descending (LAD) artery tree to coronary sinus vein and to determine its effect on the PDR and hence wall stiffness. Silicone elastomer was perfused through the LAD artery and coronary sinus trees to cast the vessels at the physiologic pressure. The results show that the physiological axial stretch exists for orders 4 to 11 (> 24 μm in diameter) arteries and orders -4 to -12 (>38 μm in diameter) veins but vanishes for the smaller vessels. Statistically, the axial stretch is higher for larger vessels and is higher for arteries than veins. The axial stretch λ(z) shows a linear variation with the order number (n) as: λ(z) = 0.062n + 0.75 (R(2) = 0.99) for artery and λ(z) = -0.029n + 0.89 (R(2) = 0.99) for vein. The mechanical analysis shows that the axial stretch significantly affects the PDR of the larger vessels. The circumferential stretch/strain was found to be significantly higher for the epicardial arteries (orders 9-11), which are free of myocardium constraint, than the intramyocardial arteries (orders 4-8). These findings have fundamental implications for coronary blood vessel mechanics.     

Biaxial vasoactivity of porcine coronary artery

The passive mechanical properties of blood vessel mainly stem from the interaction of collagen and elastin fibers, but vessel constriction is attributed to smooth muscle cell (SMC) contraction. Although the passive properties of coronary arteries have been well characterized, the active biaxial stress-strain relationship is not known. Here, we carry out biaxial (inflation and axial extension) mechanical tests in right coronary arteries that provide the active coronary stress-strain relationship in circumferential and axial directions. Based on the measurements, a biaxial active strain energy function is proposed to quantify the constitutive stress-strain relationship in the physiological range of loading. The strain energy is expressed as a Gauss error function in the physiological pressure range. In K(+)-induced vasoconstriction, the mean ± SE values of outer diameters at transmural pressure of 80 mmHg were 3.41 ± 0.17 and 3.28 ± 0.24 mm at axial stretch ratios of 1.3 and 1.5, respectively, which were significantly smaller than those in Ca(2+)-free-induced vasodilated state (i.e., 4.01 ± 0.16 and 3.75 ± 0.20 mm, respectively). The mean ± SE values of the inner and outer diameters in no-load state and the opening angles in zero-stress state were 1.69 ± 0.04 mm and 2.25 ± 0.08 mm and 126 ± 22°, respectively. The active stresses have a maximal value at the passive pressure of 80-100 mmHg and at the active pressure of 140-160 mmHg. Moreover, a mechanical analysis shows a significant reduction of mean stress and strain (averaged through the vessel wall). These findings have important implications for understanding SMC mechanics.     

Integrative control of coronary resistance vessel tone by endothelin and angiotensin II is altered in swine with a recent myocardial infarction

Several studies have indicated an interaction between the renin-angiotensin (ANG II) system and endothelin (ET) in the regulation of vascular tone. Previously, we have shown that both ET and ANG II exert a vasoconstrictor influence on the coronary resistance vessels of awake normal swine. Here, we investigated whether the interaction between ANG II and ET exists in the control of coronary resistance vessel tone at rest and during exercise using single and combined blockade of angiotensin type 1 (AT(1)) and ET(A)/ET(B) receptors. Since both circulating ANG II and ET levels are increased after myocardial infarction (MI), we investigated if the interaction between these systems is altered after MI. In awake healthy swine, coronary vasodilation in response to ET(A)/ET(B) receptor blockade in the presence of AT(1) blockade was similar to vasodilation produced by ET(A)/ET(B) blockade under control conditions. In awake swine with a 2- to 3-wk-old MI, coronary vasodilator responses to individual AT(1) and ET(A)/ET(B) receptor blockade were virtually abolished, despite similar coronary arteriolar AT(1) and ET(A) receptor expression compared with normal swine. Unexpectedly, in the presence of AT(1) blockade (which had no effect on circulating ET levels), ET(A)/ET(B) receptor blockade elicited a coronary vasodilator response. These findings suggest that in normal healthy swine the two vasoconstrictor systems contribute to coronary resistance vessel control in a linear additive manner, i.e., with negligible cross-talk. In contrast, in the remodeled myocardium, cross-talk between ANG II and ET emerges, resulting in nonlinear redundant control of coronary resistance vessel tone.     

Pulsatile blood flow in the entire coronary arterial tree: theory and experiment

The pulsatility of coronary circulation can be accurately simulated on the basis of the measured branching pattern, vascular geometry, and material properties of the coronary vasculature. A Womersley-type mathematical model is developed to analyze pulsatile blood flow in diastole in the absence of vessel tone in the entire coronary arterial tree on the basis of previously measured morphometric data. The model incorporates a constitutive equation of pressure and cross-section area relation based on our previous experimental data. The formulation enables the prediction of the impedance, the pressure distribution, and the pulsatile flow distribution throughout the entire coronary arterial tree. The model is validated by experimental measurements in six diastolic arrested, vasodilated porcine hearts. The agreement between theory and experiment is excellent. Furthermore, the present pulse wave results at low frequency agree very well with previously published steady-state model. Finally, the phase angle of flow is seen to decrease along the trunk of the major coronary artery and primary branches toward the capillary vessels. This study represents the first, most extensive validated analysis of Womersley-type pulse wave transmission in the entire coronary arterial tree down to the first segment of capillaries. The present model will serve to quantitatively test various hypotheses in the coronary circulation under pulsatile flow conditions.     

The regulatory role of oxygen radicals in myocardial cells

The paper reviews participation of primary active forms of oxygen in the processes of regulation of intracellular metabolism. Action of the primary forms of oxygen upon the myocardium contractile function depends on their concentration: their moderate increase enhances the rate and strength of contractions whereas higher concentrations diminish the contraction strength by inhibiting Ca2+ inflow from without. For NO the latter effect might be compensated by absence of coronary vessels dilatation. The level of the active forms of oxygen in the cells is subsidiary to the antioxidant system, and loss of the latter's components might trigger the apoptosis process and, consequently, some diseases.     

Functional state of the cardiovascular system in 13-year-old adolescents with different types of autonomic nervous regulation

The features of the functional state of cardiovascular system in 13-year-old children with different types of autonomic nervous regulation were studied. Children with normotonic and parasympathetic types of autonomic regulation were found to have the highest adaptation capacities. The autonomic nervous system influences the bioelectrical processes in myocardium, the duration of cardiac cycle phases, and cerebral blood flow. Schoolchildren aged 13 years with higher sympathetic activity have shorter duration of the cardiac cycle, the phase of isometric contraction, and diastole. They have a lower pulse blood flow rate and a higher tone of large and medium cerebral vessels. No relationship was revealed between the initial autonomic nervous regulation of heart rate and the type of adaptation of myocardium to physical dynamic loads, as well as the type of adaptation of cerebral circulation to mental stress.     

Effect of surrounding tissue on vessel fluid and solid mechanics

There is no doubt that atherosclerosis is one of the most important health problems in the Western Societies. It is well accepted that atherosclerosis is associated with abnormal stress and strain conditions. A compelling observation is that the epicardial arteries develop atherosclerosis while the intramural arteries do not. Atherosclerotic changes involving the epicardial portion of the coronary artery stop where the artery penetrates the myocardium. The objective of the present study is to understand the fluid and solid mechanical differences between the two types of vessels. A finite element analysis was employed to investigate the effect of external tissue contraction on the characteristics of pulsatile blood flow and the vessel wall stress distribution. The sequential coupling of fluid-solid interaction (FSI) revealed that the changes of flow velocity and wall shear stress, in response to cyclical external loading, appear less important than the circumferential stress and strain reduction in the vessel wall under the proposed boundary conditions. These results have important implications since high stresses and strains can induce growth, remodeling, and atherosclerosis; and hence we speculate that a reduction of stress and strain may be atheroprotective. The importance of FSI in deformable vessels with pulsatile flow is discussed and the fluid and solid mechanics differences between epicardial and intramural vessels are highlighted.     

Effect of passive myocardium on the compliance of porcine coronary arteries

The objective of this study was to determine the effect of passive myocardium on the coronary arteries under distension and compression. To simulate distension and compression, we placed a diastolic-arrested heart in a Lucite box, where both the intravascular pressure and external (box) pressure were varied independently and expressed as a pressure difference (DeltaP = intravascular pressure - box pressure). The DeltaP-cross-sectional area relationship of the first several generations of porcine coronary arteries and the DeltaP-volume relationship of the coronary arterial tree (vessels >0.5 mm in diameter) were determined using a video densitometric technique in the range of +150 to -150 mmHg. The vasodilated left anterior descending (LAD) coronary artery of six KCl-arrested hearts were perfused with iodine and 3% Cab-O-Sil. The intravascular pressure was varied in a triangular pattern, whereas the absolute cross-sectional area of each vessel and the total arterial volume were calculated using video densitometry under different box pressures (0, 50, 100, and 150 mmHg). In the range of positive DeltaP, we found that the compliance of the proximal LAD artery in situ (4.85 +/- 3.8 x 10-3 mm2/mmHg) is smaller than that of the same artery in vitro (16.5 +/- 6 x 10-3 mm2/mmHg; P = 0.009). Hence, the myocardium restricts the compliance of the epicardial artery under distension. In the negative DeltaP range, the LAD artery does not collapse, whereas the same vessel readily collapses when tested in vitro. Hence, we conclude that myocardial tethering prevents collapse of large blood vessel under compression.     

Viscoelastic properties of microvessels in rat spinotrapezius muscle

In order to establish a quantitative model of blood flow in skeletal muscle, the mechanical properties of the blood vessels need to be measured. We present measurements of the viscoelastic properties of arterioles, venules, and capillaries in exteriorized rat spinotrapezius muscle. Muscles were perfused with an inert silicone polymer and a uniform static pressure was established by occlusion of the venous outflow. Vessel diameters were then measured as a function of the static pressure. This study provides the first measurements of the viscoelastic properties of microvessels in skeletal muscle in situ. Over a pressure range of 20-200 mmHg, the transverse arterioles are the most distensible vessels, while the arcade venules are the stiffest. In response to a step change in pressure, all vessels show an initial elastic deformation, followed by a nonlinear creep. Based on the experimental results for different pressure histories a constitutive equation relating vessel diameter to the local transmural pressure is proposed. Diameter changes are expressed in the form of a diameter strain, analogous to a Green's strain, and are related to the local transmural pressure using a standard linear solid model. This model has only three empirical coefficients and could be fitted to all experimental results for all vessels within error of measurement.     

Participation of ATP-sensitive potassium channel in autoregulation of coronary blood flow under the condition of limited motor activity

The aim of study involved detection of the effect of the K(ATP)-channel blocker glibenclamide on autoregulation of coronary flow, the expression of reactive hyperemia, the value of coronary dilatation reserve, and the myocardial contractile function in isolated rat hearts after a 6-hour immobilization stress. The experiments have been performed on 64 isolated rat hearts (female): into the cavity of left ventricle, a latex balloon connected with electromanometer has been introduced. Every experiment consisted of 2 stages. The heart has been perfused by Krebs-Henseleite solution in the first stage, and in the second stage--by the same solution with glibenclamide (1 mkM) or its combination with verapamile (10(-)6 M) or saponin (44 mcg/ml of coronary flow within 2 minutes) added to it. During the experiment, the perfusion pressure has been elevated step by step from 40 to 120 mm Hg with 20 mm Hg steps (coronary autoregulation). In rats after immobilization, the glibenclamide effect on cardiac vessel tone and expression of maximal hyperemic coronary flow (in contrast to its influence on myocardial contractile function) is lower than in control and depends on endotheliocyte presence which suggests an important role of endothelium in maintaining cardiac vessel smooth cell activity of K(ATP)-channels inhibited under the stress condition. After immobilization stress, the role of endothelium in the reactive hyperemia origin was enhanced, that of the K(ATP)-channels was reduced. The general activity of both mechanisms of tone regulation of cardiac vessels remains the same as in control. This suggests that the K(ATP)-channels as nitric monoxide and eicozanoids are the local system of myogenic tone regulation of the rat cardiac vessels; that the rat immobilization inhibits the activity KATp-channel's smooth cells of coronary vessels and creates a marked dependence of their activity on endothelium presence.     

Rho-Rho kinase pathway is involved in the regulation of myogenic tone and pump activity in isolated lymph vessels

To evaluate whether or not Rho-Rho kinase pathway is involved in the regulation of mechanical activity of lymph vessels, effects of Y-27632 and okadaic acid on lymph pump activity and myogenic, pressure- and agonist-induced tone were examined in isolated rat lymph vessels. Y-27632 caused a significant dilation with a cessation of the lymph pump activity. Y-27632 also produced a dose-related dilation of the lymph vessels precontracted by norepinephrine (NE)-, U-46619- or 80 mM KCl. Okadaic acid significantly constricted the lymph vessels and reduced the frequency of the lymph pump activity. Okadaic acid also produced a dose-related constriction of the lymph vessels precontracted by NE or U-46619. The Y-27632-induced decrease of the frequency of lymph pump activity was significantly reversed by the pretreatment with okadaic acid. In the presence of Y-27632, the pressure-mediated tone of the lymph vessel was significantly decreased. On the other hand, okadaic acid significantly increased the pressure-mediated tone. These findings suggest that Rho kinase and myosin phosphatase activity in lymphatic smooth muscles may contribute to the regulation of lymph pump activity and may be also involved in the control of myogenic pressure- and agonist-induced tone.     

Flow Regulation in Coronary Vascular Tree: A Model Study

Background

Coronary blood flow can always be matched to the metabolic demand of the myocardium due to the regulation of vasoactive segments. Myocardial compressive forces play an important role in determining coronary blood flow but its impact on flow regulation is still unknown. The purpose of this study was to develop a coronary specified flow regulation model, which can integrate myocardial compressive forces and other identified regulation factors, to further investigate the coronary blood flow regulation behavior.

Method

A theoretical coronary flow regulation model including the myogenic, shear-dependent and metabolic responses was developed. Myocardial compressive forces were included in the modified wall tension model. Shear-dependent response was estimated by using the experimental data from coronary circulation. Capillary density and basal oxygen consumption were specified to corresponding to those in coronary circulation. Zero flow pressure was also modeled by using a simplified capillary model.

Result

Pressure-flow relations predicted by the proposed model are consistent with previous experimental data. The predicted diameter changes in small arteries are in good agreement with experiment observations in adenosine infusion and inhibition of NO synthesis conditions. Results demonstrate that the myocardial compressive forces acting on the vessel wall would extend the auto-regulatory range by decreasing the myogenic tone at the given perfusion pressure.

Conclusions

Myocardial compressive forces had great impact on coronary auto-regulation effect. The proposed model was proved to be consistent with experiment observations and can be employed to investigate the coronary blood flow regulation effect in physiological and pathophysiological conditions.     

Effects of exercise training on coronary collateralization and control of collateral resistance

Coronary collateral vessels serve as a natural protective mechanism to provide coronary flow to ischemic myocardium secondary to critical coronary artery stenosis. The innate collateral circulation of the normal human heart is typically minimal and considerable variability occurs in extent of collateralization in coronary artery disease patients. A well-developed collateral circulation has been documented to exert protective effects upon myocardial perfusion, contractile function, infarct size, and electrocardiographic abnormalities. Thus therapeutic augmentation of collateral vessel development and/or functional adaptations in collateral and collateral-dependent arteries to reduce resistance into the ischemic myocardium represent a desirable goal in the management of coronary artery disease. Tremendous evidence has provided documentation for the therapeutic benefits of exercise training programs in patients with coronary artery disease (and collateralization); mechanisms that underlie these benefits are numerous and multifaceted, and currently under investigation in multiple laboratories worldwide. The role of enhanced collateralization as a major beneficial contributor has not been fully resolved. This topical review highlights literature that examines the effects of exercise training on collateralization in the diseased heart, as well as effects of exercise training on vascular endothelial and smooth muscle control of regional coronary tone in the collateralized heart. Future directions for research in this area involve further delineation of cellular/molecular mechanisms involved in effects of exercise training on collateralized myocardium, as well as development of novel therapies based on emerging concepts regarding exercise training and coronary artery disease.     

Balance between myogenic,flow-dependent,and metabolic flow control in coronary arterial tree: a model study

Myogenic response, flow-dependent dilation, and direct metabolic control are important mechanisms controlling coronary flow. A model was developed to study how these control mechanisms interact at different locations in the arteriolar tree and to evaluate their contribution to autoregulatory and metabolic flow control. The model consists of 10 resistance compartments in series, each representing parallel vessel units, with their diameters determined by tone depending on either flow and pressure [flow-dependent tone reduction factor (TRF(flow)) x Tone(myo)] or directly on metabolic factors (Tone(meta)). The pressure-Tone(myo) and flow-TRF(flow) relations depend on the vessel size obtained from interpolation of data on isolated vessels. Flow-dependent dilation diminishes autoregulatory properties compared with pressure-flow lines obtained from vessels solely influenced by Tone(myo). By applying Tone(meta) to the four distal compartments, the autoregulatory properties are restored and tone is equally distributed over the compartments. Also, metabolic control and blockage of nitric oxide are simulated. We conclude that a balance is required between the flow-dependent properties upstream and the constrictive metabolic properties downstream. Myogenic response contributes significantly to flow regulation.