First phase microcirculatory reaction to mechanical skin irritation: a three layer model of a compliant vascular tree

Mechanical skin irritation creates vasodilatation in the line of a stroke and in the surrounding tissue. To obtain further insight on underlying physiological mechanisms we developed a model of the vascular network comprised of three layers, where the first and the last one have a tree structure. They represent the arterial and the venous system, respectively. Both are connected via an intermediate zone representing the core of the microcirculation, which is described by means of a compliant compartment model. Irritation induces change in compliance of vessels situated at the entrance of the intermediate zone. Thus the model describes flow and pressure behavior due to mechanical skin irritation.     

A morphoelastic model for dermal wound closure

We develop a model of wound healing in the framework of finite elasticity, focussing our attention on the processes of growth and contraction in the dermal layer of the skin. The dermal tissue is treated as a hyperelastic cylinder that surrounds the wound and is subject to symmetric deformations. By considering the initial recoil that is observed upon the application of a circular wound, we estimate the degree of residual tension in the skin and build an evolution law for mechanosensitive growth of the dermal tissue. Contraction of the wound is governed by a phenomenological law in which radial pressure is prescribed at the wound edge. The model reproduces three main phases of the healing process. Initially, the wound recoils due to residual stress in the surrounding tissue; the wound then heals as a result of contraction and growth; and finally, healing slows as contraction and growth decrease. Over a longer time period, the surrounding tissue remodels, returning to the residually stressed state. We identify the steady state growth profile associated with this remodelled state. The model is then used to predict the outcome of rewounding experiments designed to quantify the amount of stress in the tissue, and also to simulate the application of pressure treatments.     

A three-layer continuous model of porous media to describe the first phase of skin irritation

Mechanical skin irritation induces vasodilation on the line of scratch and in the neighboring zone. In order to model the effect of an irritation on the microcirculation, the vascular network has been described using a three-layer model. The first and last layer, considered as horizontal two-dimensional porous media, describe irrigation and drainage of the system, respectively. The intermediate layer, described by means of a lumped parameter method, does not permit horizontal fluxes. Hierarchical fluxes are directed from the first to the second layer and then towards the drainage layer in order to take into account physiological flow direction. Irritation is modeled by changing compliance of vessels situated at the entrance of the micro-circulation. The model permits to investigate the influence of change in compliance on flow and pressure behavior at microscopic and macroscopic level.     

A new fundamental bioheat equation for muscle tissue--part II: Temperature of SAV vessels

In this study, a new theoretical framework was developed to investigate temperature variations along countercurrent SAV blood vessels from 300 to 1000 microm diameter in skeletal muscle. Vessels of this size lie outside the range of validity of the Weinbaum-Jiji bioheat equation and, heretofore, have been treated using discrete numerical methods. A new tissue cylinder surrounding these vessel pairs is defined based on vascular anatomy, Murray's law, and the assumption of uniform perfusion. The thermal interaction between the blood vessel pair and surrounding tissue is investigated for two vascular branching patterns, pure branching and pure perfusion. It is shown that temperature variations along these large vessel pairs strongly depend on the branching pattern and the local blood perfusion rate. The arterial supply temperature in different vessel generations was evaluated to estimate the arterial inlet temperature in the modified perfusion source term for the s vessels in Part I of this study. In addition, results from the current research enable one to explore the relative contribution of the SAV vessels and the s vessels to the overall thermal equilibration between blood and tissue.     

In vitro studies of antigen-induced bronchospasm: effect of antihistamine and SRS-A antagonist on response of sensitized guinea pig and human airways to antigen.

Exposure of sensitized guinea pig tracheal rings or human bronchial strips to specific antigen in vitro resulted in a rapidly developing, prolonged contraction that was resistant to washing. Treatment of the tissue with diphenhydramine, a histamine H1 antagonist, before antigen delayed the onset and decreased the amplitude of the initial phase of the contraction but did not reduce the duration. Diphenhydramine treatment after development of the contraction did not relax the airway tissue. Antigen-induced histamine release from guinea pig trachea and from human bronchus was complete within the initial 15% of the duration of the contraction. Treatment of sensitized airway tissue with FPL 55712, a SRS-A antagonist, before antigen selectively inhibited the prolonged phase of the response. FPL 55712 administration after the development of antigen-induced contraction resulted in relaxation. These data suggest that both histamine and SRS-A are involved in the response of sensitized guinea pig and human airway tissue to antigen, with histamine mediating the early phase of the contraction and SRS-A primarily mediating the protracted phase.     

Coronary artery reactivity in human vessels: some questions and some answers

Spasm of a conduit coronary artery, converting it into a major resistance vessel impeding myocardial blood flow, may have severe short- or long-term effects on cardiac rhythm and systolic ejection of blood. It is now clear that human coronary arteries in vitro contract to acetylcholine but that relaxation is the only response observed in dog coronary vessels. Acetylcholine is as powerful a constrictor of human coronary arteries, in terms of tension induced, as 5-hydroxytryptamine (5-HT) or histamine and is a substantially more powerful constrictor than norepinephrine. Field stimulation of coronary artery strips caused a vasoconstriction that was partially antagonized by atropine (3.45 X 10(-6) M). An enhanced reactivity of the epicardial arteries of cardiac and older patients to several agonists was also observed and appears to provide a background against which a number of vasoactive agents might induce spasm. Coronary tissue from cardiac patients also contains stores of 5-HT and histamine, and the histamine levels are substantially increased above the values in vessels from noncardiac patients. Coronary artery spasm or contraction probably can be initiated by diverse intrinsic and extrinsic influences, including autonomic discharge from either the parasympathetic or sympathetic nervous system or from histamine or 5-HT, and probably no one agent or entity is causative in all cases.     

Effects of histamine on bronchial artery blood flow and bronchomotor tone

The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.     

Surrounding tissues affect the passive mechanics of the vessel wall: theory and experiment

The stress and strain in the vessel wall are important determinants of vascular physiology and pathophysiology. Vessels are constrained radially by the surrounding tissue. The hypothesis in this work is that the surrounding tissue takes up a considerable portion of the intravascular pressure and significantly reduces the wall strain and stress. Ten swine of either sex were used to test this hypothesis. An impedance catheter was inserted into the carotid or femoral artery, and after mechanical preconditioning pressure-cross-sectional area relations were obtained with the surrounding tissue intact and dissected away (untethered), respectively. The radial constraint of the surrounding tissue was quantified as an effective perivascular pressure on the outer surface of the vessel, which was estimated as 50% or more of the intravascular pressure. For carotid arteries at pressure of 100 mmHg, the circumferential wall stretch ratio in the intact state was approximately 20% lower than in the untethered state and the average circumferential stress was reduced by approximately 70%. For femoral arteries, the reductions were approximately 15% and 70%, respectively. These experimental data support the proposed hypothesis and suggest that in vitro and in vivo measurements of the mechanical properties of vessels must be interpreted with consideration of the constraint of the surrounding tissue.     

The Effect of Longitudinal Pre-Stretch and Radial Constraint on the Stress Distribution in the Vessel Wall: A New Hypothesis

It is well known that blood vessels shorten axially when excised. This is due to the perivascular tethering constraint by side branches and the existence of pre-stretch of blood vessels at the \textit {in situ} state. Furthermore, vessels are radially constrained to various extents by the surrounding tissues at physiological loading. Our hypothesis is that the axial pre-stretch and radial constraint by the surrounding tissue homogenizes the stress and strain distributions in the vessel wall. A finite element analysis of porcine coronary artery and rabbit thoracic aorta based on measured material properties, geometry, residual strain and physiological loading is used to compute the intramural stresses and strains. We systematically examined the effect of pre-stretch and external radial constraint in both vessels. Our results show that both stretching in the axial direction and compression in the radial direction lead to a more homogeneous strain and stress state in the blood vessel wall. A ``uniform biaxial strain' hypothesis is proposed for the blood vessel wall and the ramifications are discussed.     

Effects of granulocyte depletion on pulmonary responsiveness to aerosol histamine

The effects of granulocyte depletion with hydroxyurea on pulmonary responsiveness to aerosol histamine were studied in 10 chronically instrumented unanesthetized sheep. Sheep were studied when granulocyte counts were normal (B), after 3 days of hydroxyurea but before granulocyte counts had dropped below 700 cells/mm3 (H), and after granulocyte counts had fallen below 200 cells/mm3 (D). Hydroxyurea itself had no effect on aerosol histamine responsiveness and the results were unaffected by the order of experimentation. All 10 sheep were less responsive (P less than 0.05) to aerosol histamine when granulocyte depleted effective dose of histamine that caused a reduction to 65% of control dynamic compliance (ED65Cdyn = 23.98 +/- 4.70 mg/ml) compared with base line (ED65Cdyn = 7.06 +/- 1.86 mg/ml). Those sheep initially most responsive to aerosol histamine had the greatest attenuation in their airway responsiveness to aerosol histamine (P less than 0.05). There was a significant negative correlation between absolute granulocyte counts in peripheral blood and pulmonary responsiveness to aerosol histamine during base-line (B) condition (r = -0.74, P less than 0.05) and for the data as a whole [r = -0.69, P less than 0.05 (B + H + D)]. Circulating granulocytes and/or pulmonary inflammation may contribute to pulmonary responsiveness to bronchial challenge.     

Effects of antihistamines on the cardiopulmonary changes due to canine anaphylaxis

Histamine has long been considered to be an important chemical mediator in the pathogenesis of immediate hypersensitivity reactions. We evaluated the efficacy of antihistamines to determine the physiological role of histamine in canine anaphylaxis. Either a saline vehicle (control group), an H1 antihistamine (chlorpheniramine, 10 mg/kg), or this H1 antihistamine and an H2 antihistamine (cimetidine, 30 mg/kg) was administered to three separate groups of anesthetized dogs (n = 8). Cardiopulmonary responses and plasma histamine levels were measured after the separate intravenous injection of Ascaris suum antigen and histamine. Results were analyzed only from the animals demonstrating physiological responses or histamine release after antigen injection. In the control group, antigen produced a 43 +/- 15% (mean +/- SE) decrease in mean arterial blood pressure, a 34 +/- 13% fall in cardiac output, and a 19 +/- 9% decrease in lung compliance, whereas pulmonary vascular resistance increased 161 +/- 87% and airway resistance rose 114 +/- 66%. Similar physiological abnormalities were observed with histamine shock. However, peak plasma histamine levels were, in most cases, greater after histamine injection than after antigen injection. An H1 antihistamine alone or in combination with an H2 antihistamine did not alter the physiological changes associated with systemic anaphylaxis. In contrast, the combined use of H1 and H2 antihistamines prevented the cardiopulmonary responses associated with the intravenous administration of histamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of mechanics in vascular tissue engineering

There is a clinical need for the tissue engineering of a small diameter blood vessel substitute. Ideally such a vascular substitute should possess the functional attributes of the native vessel which it will replace. This means not only having the appropriate mechanical properties, but also being non-thrombogenic and exhibiting vasoactivity. In each of these there is in some way a role of mechanics. For thrombogenicity, an "endothelial-like" lining is required, one which is responsive to its mechanical environment in a manner similar to that of the normal vascular endothelium. If vasoactivity is exhibited, then this lining must also serve as a signal transduction interface, communicating with the underlying smooth muscle cells which themselves must be of a contractile phenotype if they are to carry out the biomechanical function resulting in contraction and dilation. Having appropriate mechanical properties means not only exhibiting sufficient strength, but also a viscoelasticity which allows for a compliance that matches that of the vascular system into which the vascular substitute is to be placed. Finally, once implanted the biological responses which will occur at least in part are regulated by biomechanical factors. Thus, the proper incorporation of biomechanics into the design of a vascular substitute is critical to achieving success.     

Activation of Rho-associated kinase during augmented contraction of the basilar artery to serotonin after subarachnoid hemorrhage

Delayed cerebral vasospasm after subarachnoid hemorrhage (SAH) may be due, in part, to altered regulation of arterial smooth muscle contraction. Contraction of cerebral arteries to serotonin is augmented after experimental SAH. We hypothesized that activation of Rho-associated kinase (Rho kinase) contributes to augmented contraction of cerebral arteries to serotonin after SAH. Autologous arterial blood (SAH) or artificial cerebrospinal fluid (control) was injected into the cisterna magna of anesthetized rabbits. At 2 days after injection, the basilar artery was excised and isometric contraction of arterial rings was recorded. Maximum contraction of the basilar artery to serotonin was augmented about fourfold in SAH compared with control rabbits (P < 0.01). Contraction to histamine was similar in the two groups. Fasudil hydrochloride (3 mumol/l), an inhibitor of Rho kinase, markedly attenuated serotonin-induced contraction. Fasudil had little effect on contractions induced by histamine or phorbol 12,13-dibutyrate. In addition, phosphorylation of myosin phosphatase, a major target of Rho kinase in regulation of smooth muscle contraction, in the basilar artery was examined by Western blotting. In basilar arteries of SAH, but not control, rabbits, serotonin increased phosphorylation of myosin phosphatase about twofold at Thr(853) of the myosin-targeting subunit. These results suggest that enhanced activation of Rho kinase contributes to augmented contraction of the basilar artery to serotonin after SAH.     

The effect of incorporating vessel compliance in a computational model of blood flow in a total cavopulmonary connection (TCPC) with caval centerline offset

BACKGROUND: The total cavopulmonary connection (TCPC), a palliative correction for congenital defects of the right heart, is based on the corrective technique developed by Fontan and Baudet. Research into the TCPC has primarily focused on reducing power loss through the connection as a means to improve patient longevity and quality of life. The goal of our study is to investigate the efficacy of including a caval offset on the hemodynamics and, ultimately, power loss of a connection. As well, we will quantify the effect of vessel wall compliance on these factors and, in addition, the distribution of hepatic blood to the lungs. METHODS: We employed a computational fluid dynamic model of blood flow in the TCPC that includes both the non-Newtonian shear thinning characteristics of blood and the nonlinear compliance of vessel tissue. RESULTS: Power loss in the rigid-walled simulations decayed exponentially as caval offset increased. The compliant-walled results, however, showed that after an initial substantial decrease in power loss for offsets up to half the caval diameter, power loss increased slightly again. We also found only minimal mixing in both simulations of all offset models. CONCLUSIONS: The increase in power loss beyond an offset of half the caval diameter was due to an increase in the kinetic contribution. Reduced caval flow mixing, on the other hand, was due to the formation of a pressure head in the offset region which acts as a barrier to flow.     

A continuum approach to blood vessel growth: Axisymmetric elastic structures

In this paper we discuss the morphogenesis of small blood vessels (venules) as the nautral consequence of physical forces prevailing during endothelial cell division. A physical model is developed in which the blood vessel is treated as a growing, thin elastic shell embedded in a viscous fluid (i.e. the surrounding tissue). It is explained how a pre-existing cylindrical vessel, induced to grow by some promoter, can buckle and thereby develop a spatially periodic structure displaying varicosity, sinuosity, and/or helicity. Growth manifests itself dynamically in terms of a “growth pressure” which disturbs any pre-existing force balance. The governing set of non-linear partial differential equations are derived, and solutions corresponding to uniform dilation are obtained. The buckled structure emerges as an instability of this time dependent basic state of uniform dilation. A linear stability analysis yields the dominant wavelength of the varicose mode; these results compare favorably with crude measurements made from the experimental literature. In the hope of uncovering the mechanism which underlies the selection of sprouting sites along a parent vessel, it is suggested that reaction and diffusion processes (between growth promoting and inhibiting substances) on buckled surfaces be coupled to the dynamical force balances discussed here.     

Effect of histamine and cimetidine on retinal and choroidal blood flow in humans

Intravenous administration of histamine causes an increase in choroidal blood flow and retinal vessel diameter in healthy subjects. The mechanism underlying this effect remains to be elucidated. In the present study, we hypothesized that H2 receptor blockade alters hemodynamic effects of histamine in the choroid and retina. Eighteen healthy male nonsmoking volunteers were included in this randomized, double-masked, placebo-controlled two-way crossover study. Histamine (0.32 microg.kg(-1).min(-1) over 30 min) was infused intravenously in the absence (NaCl as placebo) or presence of the H2 blocker cimetidine (2.3 mg/min over 50 min). Ocular hemodynamic parameters, blood pressure, and intraocular pressure were measured before drug administration, after infusion of cimetidine or placebo, and after coinfusion of histamine. Subfoveal choroidal blood flow and fundus pulsation amplitude were measured with laser-Doppler flowmetry and laser interferometry, respectively. Retinal arterial and venous diameters were measured with a retinal vessel analyzer. Retinal blood velocity was assessed with bidirectional laser-Doppler velocimetry. Histamine increased subfoveal choroidal blood flow (+14 +/- 15%, P < 0.001), fundus pulsation amplitude (+11 +/- 5%, P < 0.001), retinal venous diameter (+3.0 +/- 3.6%, P = 0.002), and retinal arterial diameter (+2.8 +/- 4.2%, P < 0.01) but did not change retinal blood velocity. The H2 antagonist cimetidine had no significant effect on ocular hemodynamic parameters. In addition, cimetidine did not modify effects of histamine on choroidal blood flow, fundus pulsation amplitude, retinal venous diameter, and retinal arterial diameter compared with placebo. The present data confirm that histamine increases choroidal blood flow and retinal vessel diameters in healthy subjects. This ocular vasodilator effect of histamine is, however, not altered by administration of an H2 blocker. Whether the increase in blood flow is mediated via H1 receptors or other hitherto unidentified mechanisms remains to be elucidated.     

On the effect of preload and pre-stretch on hemodynamic simulations: an integrative approach

In this work, we address the simulation of three-dimensional arterial blood flow and its effect on the stress state of arterial walls. The novel contribution is the unprecedented combination of several modeling techniques to account for (1) the fact that known configurations for the arterial wall are in a preloaded state, (2) the compliance of the vessel segments, (3) proper boundary data over the non-physical interfaces resulting from the isolation of an arterial district from the rest of the arterial tree, (4) the presence of surrounding tissues in which the vessel is embedded and (5) residual stress state due to pre-stretch. Firstly, we formulate both the forward mechanical problem when the reference (zero-load) configuration is assumed to be known and, the preload problem arising when the known domain is a configuration at equilibrium with a certain load state (typically due to internal pressure and tethering forces). Then, two additional complexities are faced: the fluid–structure interaction problem that follows when the compliant vessels are coupled with the blood flow, and the introduction of non-physical boundaries coming from the artificial isolation of the arterial district from the original vessel. This, in turn, posses the problem of coupling dimensionally heterogeneous models to incorporate the effect of upstream and downstream systemic impedances. Additionally, a viscoelastic support on the external surface of the vessel is also incorporated. Two examples are presented to quantify in a physiologically consistent scenario the differences in simulation results when either considering or not the preload state of arterial walls. These computational simulations shed light on the validity of simplifying hypotheses in most hemodynamic models.     

Effect of wall compliance and permeability on blood-flow rate in counter-current microvessels formed from anastomosis during tumor-induced angiogenesis

Tumor blood-flow is inhomogeneous because of heterogeneity in tumor vasculature, vessel-wall leakiness, and compliance. Experimental studies have shown that normalization of tumor vasculature by antiangiogenic therapy can improve tumor microcirculation and enhance the delivery of therapeutic agents to tumors. To elucidate the quantitative relationship between the vessel-wall compliance and permeability and the blood-flow rate in the microvessels of the tumor tissue, the tumor tissue with the normalized vasculature, and the normal tissue, we developed a transport model to simultaneously predict the interstitial fluid pressure (IFP), interstitial fluid velocity (IFV) and the blood-flow rate in a counter-current microvessel loop, which occurs from anastomosis in tumor-induced angiogenesis during tumor growth. Our model predicts that although the vessel-wall leakiness greatly affects the IFP and IFV, it has a negligible effect on the intravascular driving force (pressure gradient) for both rigid and compliant vessels, and thus a negligible effect on the blood-flow rate if the vessel wall is rigid. In contrast, the wall compliance contributes moderately to the IFP and IFV, but significantly to the vessel radius and to the blood-flow rate. However, the combined effects of vessel leakiness and compliance can increase IFP, which leads to a partial collapse in the blood vessels and an increase in the flow resistance. Furthermore, our model predictions speculate a new approach for enhancing drug delivery to tumor by modulating the vessel-wall compliance in addition to reducing the vessel-wall leakiness and normalizing the vessel density.     

Lymphatic vessels transition to state of summation above a critical contraction frequency

Although behavior of lymphatic vessels is analogous to that of ventricles, which completely relax between contractions, and blood vessels, which maintain a tonic constriction, the mixture of contractile properties can yield behavior unique to lymphatic vessels. In particular, because of their limited refractory period and slow rate of relaxation, lymphatic vessels lack the contractile properties that minimize summation in ventricles. We, therefore, hypothesized that lymphatic vessels transition to a state of summation when lymphatic vessel contraction frequency exceeds a critical value. We used an isovolumic, controlled-flow preparation to compare the time required for full relaxation with the time available to relax during diastole. We measured transmural pressure and diameter on segments of spontaneously contracting bovine mesenteric lymphatic vessels during 10 isovolumic volume steps. We found that beat-to-beat period (frequency(-1)) decreased with increases in diameter and that total contraction time was constant or slightly increased with diameter. We further found that the convergence of beat-to-beat period and contraction cycle duration predicted a critical transition value, beyond which the vessel does not have time to fully relax. This incomplete relaxation and resulting mechanical summation significantly increase active tension in diastole. Because this transition occurs within a physiological range, contraction summation may represent a fundamental feature of lymphatic vessel function.