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Effect of a flavonoid preparation (S 5682) on experimental capillary permeability increase in rat paw and rabbit skin.

S 5682 is constituted by a flavonoid mixture of 90% diosmin and 10% hesperidin. Its action has been studied in vivo on microcirculation by measuring experimental alterations of capillary permeability and of venous pressure. Rats were pretreated by IV injection of 25 mg S 5682/kg, one hour before being submitted to a transitory compression of the posterior paw, resulting in reversible oedema that was estimated by plethysmography. The swelling of the paw in pretreated rats was lower than in controls (p less than 0.02), indicating a smaller increase of capillary permeability in rats treated with S 5682. A direct action on capillary permeability has been examined by measuring accumulation of IV injected Evans blue at the site of injection of zymosan, this accumulation was lower in pretreated rats than in controls (p less than 0.05). Similarly, in CFY rats, the pressure required to evoke capillary fragilisation was higher in S 5682 pretreated rats. Evans blue extravasation was also studied in the rabbit in which skin was irritated by topical application of chloroform of by gamma rays. Subcutaneous accumulation of Evans blue was lower in animals pretreated either IV or by oral route than in controls (p less than 0.05). S 5682 has a complex effect on microcirculation as indicated by a smaller increase in femoral venous pressure after ligation of homolateral iliac vein. The above experimental results indicate that S 5682 is acting at the venous side of the microcirculation.

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Capillary permeability of rabbit ovarian follicles prior to ovulation.

Ultrastructurally, three possible pathways of capillary permeability were observed during the ovulatory process in rabbit ovarian follicles treated with human chorionic gonadotrophin: namely, pinocytotic vesicles, fenestrations, and interendothelial gaps. The increased permeability of perifollicular capillaries just prior to ovulation was confirmed as being primarily due to the formation of gaps, using carbon particles as a tracer.

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CT measurements of capillary permeability within nodal masses: a potential technique for assessing the activity of lymphoma.

Analysis of time-attenuation data has enabled CT to measure capillary permeability within the brain and kidney. As yet, such techniques have not been applied to nodal masses in patients with lymphoma. Tumour angiogenesis is known to produce capillaries that exhibit increased permeability and CT measurements of permeability could therefore potentially provide a marker of tumour viability. This study aims to determine the feasibility and limitations of CT measurement of capillary permeability within lymphoma nodal masses. Six patients with biopsy proven lymphoma have been studied. Time-attenuation curves from the aorta and nodal mass were generated from a single-location dynamic sequence of images acquired over 3 min following an intravenous bolus of iopamidol. A nuclear medicine data processing technique, Patlak analysis, was used to calculate capillary permeability and blood volume within the nodal mass. Renal blood vessel permeability was also determined in four patients. Median lymph node permeability to iopamidol was 88.5 microliters min-1 ml-1 (range 36.4-198.5 microliters min-1 ml-1). The correlation coefficient of the linear fit for the Patlak analysis ranged from 0.74 to 0.95 and was greater than 0.9 for regions of interest of 150 pixels or more (256 x 256 matrix). The values for renal permeability (442 microliters min-1 ml-1; range: 349-589 microliters min-1 ml-1) were comparable to those previously reported. Functional images of permeability were also obtained. The study has confirmed the feasibility of CT measurements of capillary permeability within nodal masses. The technique combines anatomical imaging and functional information within one examination and has potential application in monitoring the response of lymphoma to therapy.

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Patterns of change in endoneurial capillary permeability and vascular space during Wallerian degeneration.

In degenerating frog sciatic nerves an in situ perfusion technique was used to measure the permeability coefficient-surface area product (PA) of endoneurial capillaries to [14C]sucrose, and the endoneurial vascular space (V). Both PA and V started to increase after the 3rd day of degeneration. The increase in PA peaked around the 14th day of degeneration and then declined to reach near normal levels at 6 weeks post-transection. V increased until about the end of the 3rd week of degeneration and then declined to near normal levels at 6 weeks after transection. The delayed increase in capillary permeability may reflect an adaptive reorganization of endoneurial capillary structure and function in response to altered conditions of the endoneurial microenvironment, and it is suggested that this permeability increase is induced by breakdown products of axons or chemical signals from Schwann cells enveloping transected axons. Fluid extravasation from these leaking capillaries is probably responsible for the endoneurial oedema observed in Wallerian degeneration. The recovery of endoneurial capillary tone to near-normal levels at 6 weeks after transection leads to the intriguing conclusion that healthy nerve fibers are not essential for the maintenance of normal endoneurial capillary permeability.

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The role of blood coagulation in capillary permeability Vitalmicroscopic contributions.

It is our concept that the blood coagulation and fibrinolytic systems contribute to capillary permeability. By means of fluorescent intravital microscopy we measured in situ the permeability of proteins and fluorescent tracers through the walls of various kinds of microvessels (exposed rat mesentery). Fluorescent dyes applied intravenously pass across the walls of all kinds of microcirculatory vessels into the perivascular tissue in animals having a state of hypocoagulemia in a shorter time than in normals. Fluorescent-tagged fibrinogen accumulates at the vascular wall, especially at the inner lining of venules, thus marking free receptor sites for fibrinogen at these places. Blocking the fibrinolytic activity of the blood augments the fibrinogen deposition. Pretreatment by heparin does not prevent it, which speaks against the fibrinogen-fibrin coagulation during the accumulation phenomenon. In contrast to this behavior of fibrinogen, albumin, gammaglobulin, antithrombin III, plasminogen never accumulate at the vessel wall but pass through the vascular wall, mostly at venules. The speed and amount of the transvascular passage of these proteins depends on their molecular weight. Fibronectin shares the same receptor sites at the inner lining of microcirculatory vessels as fibrinogen. It seems possible, therefore, that both proteins, fibrinogen and fibronectin, interact with each other at the endo-endothelial cell border. A low molecular weight polypeptide fraction of factor VIII accumulates at the vascular wall similar to fibrinogen. At the same time it decreases the capillary permeability for serum proteins.

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The influence of the sympathetic nervous system on capillary permeability.

1. The influence of the sympathetic nervous system on capillary permeability was studied in cats. The dye penetration from the blood through the synovial membrane was tested by perfusing the two knee joints, one of which was deprived of its sympathetic nerve supply by unilateral lumbosacral sympathectomy. 2. In confirmation of previous experiments, it was found in a great majority of experiments that, in spite of marked vasodilatation, the dye excretion was considerably reduced on the sympathectomised side. 3. A large amount of experimental evidence, supporting directly or indirectly, my views, has been reviewed. 4. A permeability factor under the influence of the sympathetic nervous system has been postulated; its character and mechanism is still unknown. 5. Further unpublished experiments seem to support the view that increased blood supply is associated with decreased vascular permeability.

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Diabetic microangiopathy treated with elastic compression--a microcirculatory evaluation using laser-Doppler flowmetry, transcutaneous PO2/PCO2 and capillary permeability measurements.

One hundred and forty patients with diabetic microangiopathy were studied by laser-Doppler flowmetry--measuring skin blood flow at rest (RF) and the venoarteriolar response (VAR)--by transcutaneous PO2 and PCO2 measurements and by evaluation of capillary permeability (rate of ankle swelling = RAS). Seventy were treated for 12 months with below-knee, elastic stockings. Seventy patients were left without compression acting as a control group. After 5 and 12 months there were no significant changes in the control group. However there was a significant improvement of microcirculatory parameters in patients treated with elastic compression. RF (increased at the beginning of the study) decreased. The VAR (impaired at the beginning of the study) improved significantly. PO2 (increased after treatment) and PCO2 (decreased) were also positively changed by elastic stockings. The abnormally increased capillary permeability was also improved. Elastic compression seems to be useful in diabetic microangiopathy improving microcirculatory parameters and decreasing capillary permeability and edema. However further studies, treating with elastic compression more patients for longer periods, are needed to confirm the positive effects of elastic stockings in improving diabetic microangiopathy and in slowing down its rate of progression.

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Vascular endothelial growth factor expression, vascular volume, and, capillary permeability in human brain tumors.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and a potent inducer of vascular permeability. In this study, we determined whether expression of VEGF is correlated with in vivo measurements of the capillary permeability and vascular volume of primary human brain tumors. METHODS: Tumor samples (seven glioblastomas, one anaplastic astrocytoma, two low-grade astrocytomas, one pilocytic astrocytoma, and three primary cerebral lymphomas) were stereotactically obtained from 14 patients. A semiquantitative polymerase chain reaction was used to quantify the relative expression of VEGF messenger ribonucleic acid in the tumors. VEGF protein was demonstrated in tissue sections by immunohistochemical techniques. A two-compartment dynamic computed tomographic method was used to quantitatively measure the aforementioned parameters in the regions from which the biopsies were obtained. RESULTS: In glial tumors, there was significant correlation of VEGF messenger ribonucleic acid levels with capillary permeability (P < 0.05) and vascular volume (P < 0.01). Although all primary cerebral lymphomas showed considerable increases in capillary permeability and vascular volume, VEGF expression was only slightly upregulated in these tumors. CONCLUSION: Our findings are consistent with the hypothesis that VEGF may be responsible for endothelial cell proliferation and vascular permeability in glial tumors. This relationship has implications for clinical applications, i.e., assessment of delivery of water-soluble drugs, treatment of edema, and antiangiogenesis therapy based on inhibition of VEGF function.

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Transcapillary escape rate and capillary permeability to albumin in patients with Plasmodium falciparum.

The transcapillary escape rate and capillary permeability to albumin were studied in five patients with Plasmodium falciparum malaria and six control subjects by using 125I-HSA. The mean transcapillary escape rate of albumin, calculated from the slope of the plasma disappearance curve of 125I-HSA, was found to be significantly higher in the malaria patients than in the control group. As the plasma volume increased while the plasma albumin concentration decreased in these patients, this resulted in a significantly higher plasma clearance and outflux of albumin from the intravascular to the extravascular compartments. Both the effective capillary pore area per unit path length available for restricted diffusion and the specific permeability coefficient of the capillary to albumin were found to be grossly elevated in the patients' group. These findings indicated that there was an increased leakage of plasma albumin in patients with P. falciparum malaria as a result of increased capillary surface area and an increased capillary permeability to albumin.

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A multi-organ, axially distributed model of capillary permeability for a magnetic resonance imaging contrast agent.

Capillary permeability was resolved from uptake data for eight rat organs with gadoteridol, which is a stable, well-tolerated, nonionic, highly water soluble, gadolinium-containing, magnetic resonance imaging contrast agent. The extracellular kinetics were elucidated with an axially distributed, plasma interstitial fluid model and measured plasma flow, organ plasma volume, and interstitial fluid volume. The molecular and biological properties of gadoteridol and this kinetic model provide magnetic resonance imaging with a tool to begin measuring physiologic processes.

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Leucocyte depletion attenuates the early increase in myocardial capillary permeability to small hydrophilic solutes following ischaemia and reperfusion.

OBJECTIVE: The aim was to assess the significance of polymorphonuclear leucocytes on the myocardial capillary permeability to a small hydrophilic indicator, on the vascular tone of the resistance vessels, and on contractile function following ischaemia and reperfusion. METHODS: Open chest, anaesthetised dogs were randomised to treatment with polyclonal antibody against polymorphonuclear leucocytes (anti-PMN group) or non-specific antibody (control group), and subjected to 40 min of coronary occlusion followed by 3 h of reperfusion. The capillary extraction fraction and the myocardial plasma flow rate were quantitated in vivo by intracoronary indicator bolus injection and external registration of the washout, and the capillary permeability-surface area product was calculated. Postischaemic vasodilator tone in the myocardial resistance vessels was measured by the local 133xenon washout method. RESULTS: 20 dogs were included (10 in each group), and 13 dogs completed the ischaemia-reperfusion protocol (anti-PMN group, n = 7; control group, n = 6). In the anti-PMN group, blood polymorphonuclear leucocyte counts were reduced to a minimum of 15% of pretreatment values. After ischaemia and 5 min reperfusion, the capillary extraction increased by 17% in the control group but decreased by 22% in the anti-PMN group (p < 0.05). The corresponding capillary permeability-surface area product increased by 22% in the control group, but decreased by 16% in the anti-PMN group (p < 0.05). Neither maximum myocardial plasma flow during reactive hyperaemia nor contractile function were influenced by anti-PMN treatment. CONCLUSIONS: Polymorphonuclear leucocytes appear to participate in the increase in myocardial capillary permeability observed early after reperfusion following a 40 min period of ischaemia, but do not influence postischaemic vascular tone or postischaemic contractile function. During normal physiological conditions reduction of the circulating polymorphonuclear leucocyte counts did not induce significant changes in myocardial capillary permeability.

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Long-term antidepressant treatment: alterations in cerebral capillary permeability.

Chronic treatment of rats with amitriptyline (AMI) induced a persistent increase in the diffusibility of water into the brain (EW). This effect was observable 12 h after the last dose. AMI induces this alteration at plasma drug concentrations of 71 +/- 13 ng/ml (the therapeutic range for man is 100--250 ng/ml). Furthermore, chronic treatment potentiated the increase observed after acute drug administration and resulted in a 350% enhancement in the permeability of water across the cerebral capillary. Thus, long-term antidepressant administration can chronically influence cerebral function by affecting capillary permeability.

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Effect of local arterial hypotension on cat intestinal capillary permeability.

The effects of local arterial hypotension on lymph flow, lymphatic protein flux, and capillary permeability were analyzed in an isolated vascularly perfused cat ileum preparation. Reductions in perfusion pressure to 30-40 mmHg (60 min) resulted in a lowering of lymph flow and an increase in the lymph to p lasma protein concentration ratio. Release of the partial arterial occlusion caused lymph flow and lymph to plasma protein concentration ratio to increase above their control values. Venous outflow pressure was then increased in 10 mmHg increments to 30 mmHg. The capillary osmotic reflection coefficient was estimated from the relationship between lymph to plasma protein concentration ratio and lymph flow. Values of the osmotic reflection coefficient for total proteins and individual protein fractions were significantly lower than control values. The results of this study indicate that 1 hr of regional ischemia significantly increases the permeability of intestinal capillaries. The increased capillary permeability accounts, at least in part, for the enhanced capillary filtration and interstitial fluid accumulation which occurs in the posthypotensive small intestine.

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Peritubular capillary permeability and intravascular RBC aggregation after ischemia: effects of neutrophils.

The influence of neutrophils on peritubular capillary permeability and intravascular red blood cell (RBC) aggregation after renal ischemia was studied in anesthetized Sprague-Dawley rats. Intraperitoneal administration of antineutrophil serum (ANS) reduced the number of neutrophils in the blood to 3% of normal. The control group received an equal volume of inactive serum. Renal macromolecular capillary permeability was studied from 1) extravasation of albumin and 2) plasma to lymph transport of plasma proteins and of neutral and negatively charged lactate dehydrogenase (LDH). The net driving force (NDF) for fluid transfer over the peritubular capillary membrane was determined by the micropuncture technique. The intrarenal distributions of neutrophils and RBC were measured by a histochemical method and 51Cr-labeled RBC, respectively. Under preischemic control conditions neither macromolecular permeability nor renal clearance of inulin was affected by ANS. However, the steep increase in the macromolecular transport from plasma to lymph resulting from 45 min of ischemia and reperfusion was blunted by ANS, and preischemic control values were restored after 1 h of recirculation. In the control group the mass transport of plasma proteins increased twofold and that of both neutral and negatively charged LDH fourfold. NDF was equal in the two groups. In the ANS-treated animals the intrarenal neutrophil content was only 2% of the control. Neutrophils were found mainly in the cortex, whereas RBC aggregation was observed only in the renal medulla. It is concluded that neutrophils mediate postischemic capillary leakage. It is suggested that this leakage underlies RBC aggregation and incomplete return of blood flow in the renal medulla after ischemia.

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Capillary permeability of sulphate-substituted and neutral dextran fractions in the rat hindquarter vascular bed.

In order to investigate the impact of molecular charge on capillary permeability to macromolecules, capillary reflection coefficients (sigma) for various concentrations of two neutral dextran fractions (Mw 70 000 and 139 000) and one negatively charged, sulphate-substituted dextran fraction (Mw 109 000) were determined in the isolated perfused rat hindquarter preparation, during stable haemodynamic conditions. The capillary reflection coefficient was calculated as the ratio between the estimated colloid osmotic pressure in vivo, determined by an osmotic transient technique, and that in vitro, measured with an osmometer. Despite its intermediate size the sulphated dextran (D 109-S) showed a markedly higher sigma than the two neutral ones (D 70 and D 139) and, further, whereas sigma for D 70 and D 139 decreased with increasing dextran concentration, sigma for D 109-S remained constant over the whole range of concentrations investigated. At dextran concentrations equivalent to an in vivo colloid osmotic pressure of 23.5 mmHg, sigma averaged 0.901 for D 109-S, compared with 0.547 and 0.693 for D 70 and D 139, respectively, and with 0.87 for albumin in normal plasma. It is suggested that capillary macromolecular permeability is due to both structural and electrophysical properties of the microvascular barrier, where negative charges of the endothelial glycocalyx and of wall-adsorbed plasma proteins cause repulsion of circulating large polyanions.

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