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PubMed1978

Vascular permeability and neurotoxicity.

Neurotoxic substances affect the nervous system in a selective manner. One possible basis for this selectivity is blood vessel permeability. In general, the central nervous system and the peripheral nerve trunks have impermeable blood vessels, but in certain parts the capillaries are "leaky," allowing the passage of a plasma filtrate. Intravenously injected protein tracers rapidly reach nerve cells in these regions, with the implication that these nerve cells are also readily accessible to circulating neurotoxic substances. Some examples of neurotoxicity in the central nervous system show a selectivity that could be due to capillary permeability. In experimental methylmercury poisoning, cranial nerve V and sensory dorsal root ganglia, which lie in regions of vascular permeability, are particularly susceptible. A number of drug and chemically induced neuropathies are predominantly sensory, and may be due, directly or indirectly, to the accessibility of neurotoxic substances to sensory neurons. Examination of areas of potential vulnerability to circulating toxic substances may be of value in the experimental testing of substances for neurotoxicity, where pharmacological tests may be negative and clinical symptoms difficult to assess.

Animals↗

PubMed1977

Absence of restricted diffusion in cutaneous capillaries.

Capillary permeability in cutaneous tissue for 57Co-cyanocobalamin (57 Co-B12) was determined by the single injection, external registration method. The capillary diffusion capacity, CDC (the permeability--surface area product, PS) was 2.3 ml/100 g-min. Capillary extraction was 0.48 at a plasma flow of 4.1 ml/100 g-min. Results were compared to 51Cr-EDTA data from a previous study with identical method and preparation. As CDC(51Cr-EDTA)/CDC(57Co-B12) was 1.61 and as D(51Cr-EDTA)/D(57Co-B12), the ratio between the free diffusion coefficients in water at 37 degrees C, was 1.79 it is concluded that restricted diffusion does not occur in cutaneous tissue for 57Co-B12 as compared to 51Cr-EDTA, i.e. 51Cr-EDTA and 57Co-B12 diffuse across the capillary membrane of cutaneous tissues at rates proportional to their respective free diffusion coefficients in water. The Pappenheimer equivalent pore radius estimate of 30 A and the Karnovsky interendothelial 40 A slit width are both defective in explaining the experimental data. The transendothelial patent channel system of fused vesicles (Simionescu, Simionescu and Palade 1975) is a possible structural equivalent for the present findings. The results support the hypothesis that capillaries of continuous type exhibit similar permeation characteristics regardless of the tissue in which they are located.

Animals↗

PubMed1991

Participation of collagenase and elastase in LPS-induced airway hyperresponsiveness in guinea pigs.

Bacterial lipopolysaccharide (LPS) cause airway hyperreactivity in guinea pigs pretreated with metopirone. LPS inhalation resulted in an increase in airway muscarinic reactivity measured by intravenous acetylcholine injection 1-4 h after the inhalation of LPS. The increase of pulmonary capillary permeability was observed 1-24 h after the inhalation of LPS, whereas the increase of leukocytes in bronchoalveolar lavage fluid (BALF) was observed 2 and 24 h after the inhalation of LPS. Increased cells are mainly neutrophil, eosinophil, and macrophage. From the histopathological study, acute mucosal injury and loss of epithelial cilia were observed 1-24 h after the inhalation of LPS. In order to investigate the phlogistic substance in LPS-induced hyperreactivity, the roles of collagenase and elastase were investigated. The activities of both enzymes were elevated 2 h after the inhalation of LPS. The inhalation of collagenase and elastase caused bronchial hyperreactivity and increased pulmonary permeability. The combined administration of prednisolone (10 mg/kg/day) and cyclophosphamide (10 mg/kg/day) for five days decreased LPS-induced hyperreactivity, pulmonary capillary increase, collagenase and elastase activities, and the number of nucleated cells in BALF 2 h after the inhalation of LPS. These results indicate the participation of collagenase and elastase in the onset of LPS-induced airway hyperreactivity in guinea pigs.

Acetylcholine↗

PubMed1977

[Coagulation factors in human born blisters (author's transl)].

Following clotting factor assays were performed on the fluid of burn blisters of 11 patients with severe burns: Fibrinogen levels, Factor II, V, X and XIII, thrombin time, fibrin split products, plasminogen, antithrombin III, IgA, IgM, IgG, ethanol gelation test and total proteins. The results showed, that a quantity of Factor II, X and XIII, antithrombin III, plasminogen and IgG had left the circulation. On the contrary we found only small concentrations of Factor V, fibrinogen, IgM and IgA in the fluid of burn blisters. This distribution suggested that the losses of plasma proteins into the burn blisters were correlated to their concentration and their molecular weight. The decrease of plasma coagulation proteins during the first days after severe burns was probably partly due to losses through the walls of the vessels, because of the increased capillary permeability.

Antithrombins↗

PubMed1976

Renal cortical blood flow in glycerol-induced acute renal failure in the rat.

Renal hemodynamics and renal function were evaluated in rats at 3, 24, and 48 hours and at 7 days after the induction of acute renal failure (ARF) by glycerol injection. Three hours after induction of ARF, creatinine clearance was 0.04 ml/min/100 g; renal blood flow (RBF), 1.99 ml/min/100 g; and filtration fraction, 3.7%. All were abnormally low. Although the administration of isotonic saline (total dose, 3% of body weight) to rats 3 hours after glycerol injection significantly improved creatinine clearance (0.17 ml/min/100 g), RBF (2.54 ml/min/100 g), and filtration fraction (12.9%), these values still were significantly lower than those of controls (creatinine clearance = 0.50 ml. ml/min/100 g, RBF = 4.92 ml/min/100 g, filtration fraction = 20.0%, all P values less than 0.001). Serum creatinine concentrations were significantly elevated at 24 hours (3.72% gm/100 ml), 48 hours (4.69 mg/100 ml), and 7 days (0.66 mg/100 ml) after glycerol injection compared to control (0.46 mg/100 ml, all P less than 0.01). RBF during these phases was not different from normal (4.41 ml/min/100 g). RBF 3 hours after bilateral ureteral obstruction was measured to determine the effects of tubular obstruction on renal hemodynamics. The RBF of rats with ureteral obstruction (4.12 ml/min/100 g) was not significantly different from controls (4.41 ml/min/100 g), suggesting that tubular obstruction in this model of ARF is probably not the cause of decreased RBF. The depressed glomerular filtration, as reflected by the decreased creatinine clearance that occurs during glycerol-induced ARF, is probably related to altered intrarenal vascular resistance or to changes in glomerular capillary permeability, or both.

Acute Kidney Injury↗

PubMedDate not supplied

Permeability of synovial membrane to plasma proteins in human coxarthrosis: relation to molecular size and histologic changes.

The ratios of synovial fluid concentration to serum concentration (SF/S) for 4 nonimmunoglobulin proteins were higher in osteoarthritic synovia than in normal. The difference increased with increasing molecular weight and was highly significant for the largest molecules. An almost inverse linear relationship was observed between SF/S ratios of the proteins and their molecular weight. As only slight signs of inflammation were found in the osteoarthritic synovium, no correlation could be demonstrated between ratio and the degree of synovial inflammation as assessed by histologic methods. Two types of synovitis were encountered in patients with osteoarthritis: an early "proliferative" stage, characterized by synovial edema and large numbers of dilated venules and capillaries and a later "fibrous" stage characterized by scarring of the synovium. The highest ratios corresponded to the proliferative type. The abnormal protein pattern in osteoarthritic synovia is a result of increased capillary permeability in the synovial membrane owing to capillary dilation and stasis.

Capillary Permeability↗

PubMed2000

In vivo measurement of lung capillary-alveolar macromolecule permeability by saturation bronchoalveolar lavage.

OBJECTIVE: Measurement of capillary-alveolar permeability to fluorescein isothiocyanate-dextran (FITC-D) (molecular mass, 71,300 daltons) by a sequential bronchoalveolar lavage (BAL) technique. DESIGN: Animal research. SETTING: The Department of Physiology at a scientific and medical university. SUBJECTS: Nine anesthetized and mechanically ventilated dogs. INTERVENTIONS: Two separate experiments were performed in each subject-an initial control experiment followed by an oleic acid-induced lung injury. The indicator was administered at constant blood concentration before serial BAL including eight fluid instillation-recovery cycles. MEASUREMENTS: Plasma to BAL solute clearance at saturation (capillary-alveolar clearance at saturation, mL/min) was calculated and normalized to lavage fluid volume (measured by 1251 serum albumin dilution) to obtain a transport rate (TR) constant. MAIN RESULTS: TR for FITC-D70 was 4.0+/-0.8 and 46.1+/-18.1 x 10(-5) x min(-1) in control and injured lung, respectively (p < .02). Capillary-alveolar clearance of FITC-D70 was not affected by the lavage procedure itself. TR reflected essentially epithelial permeability in normal lung and combined epithelial and endothelial permeability in injured lung. A significant correlation was found between cardiac output and TR in injured lung. CONCLUSIONS: Saturation BAL allowed us to estimate capillary-alveolar macromolecule permeability in vivo in dogs. Further study may allow bedside evaluation of lung injury by BAL in patients.

Animals↗

PubMed1985

Leukotriene- and histamine-induced increases in vascular permeability and interstitial transport in the skin.

The aim of the present study was to investigate the edema induced by leukotriene D4 (LTD4). Edema is the gross effect of increased blood flow and capillary permeability. Our objective was to elucidate the effect of LTD4 on edema generation without the influence of the concomitantly increased blood flow induced by this potent vasodilator. A new method was outlined measuring the exudation through skin windows of a macromolecular tracer [( 131I]albumin) and a micromolecular tracer [( 99Tc]pertechnetat). Exudation of [131I]albumin is a function of enhanced vascular permeability and interstitial transport and blood flow, whereas that of [99Tc] pertechnetat is mainly a function of blood flow. Thus a ratio of the 2 exudate measurements gives a specific estimate of the changes in vascular permeability and interstitial transport. Histamine was employed to establish the method. A dose-response relation was found for histamine in the dose range of 10(-4) to 10(-7) M. The effect of 10(-5) M LTD4 on vascular permeability and interstitial transport of macromolecules was indistinguishable from that of histamine in the same concentration. This property together with their well-known vasodilatory capabilities indicate that the leukotrienes of the slow-reacting substance of anaphylaxis may play a role in the vascular changes in the allergic-inflammatory reaction.

Adult↗

PubMed1995

Computed tomography evaluation of regional increases in microvascular permeability after reperfusion of locally ischemic myocardium in intact pigs.

RATIONALE AND OBJECTIVES: I evaluated how well fast computed tomography (CT) scanning could quantify altered myocardial microvascular function resulting from transient ischemia and subsequent reperfusion. METHODS: A major epicardial coronary artery of anesthetized pigs was occluded for either 0, 15, 30, 60, or 120 min. Fast X-ray CT scan sequences were performed before and during occlusion and 30, 60, and 90 min after onset of subsequent reperfusion. Regional myocardial perfusion, intramyocardial blood volume, and myocardial microcirculatory permeability-surface area product were estimated from the CT scan sequences. RESULTS: With the increasing duration of ischemia, the permeability-surface area product remained unchanged during reperfusion (p > .05), but an index of myocardial microvascular permeability increased with the progressive duration of ischemia and of reperfusion (p < .05). CONCLUSION: These CT-based findings are consistent with published, more invasive demonstrations that capillary permeability is increased during postischemic reperfusion in proportion to the duration of the preceding ischemia.

Animals↗

PubMedDate not supplied

Permeability of muscle spindle capillaries and capsule.

The permeability of capillaries in rabbit muscle spindles, intramuscular nerves, and extrafusal muscle to intraaortically infused horseradish peroxidase (HRP) was studied. The permeability of the capsule cells of the muscle spindles was also examined. Immediately following the infusion of HRP, most extrafusal capillaries contained a dense accumulation of HRP reaction product, which began to escape into the surrounding extracellular space within 2-3 min. In contrast, the concentration of HRP in the intrafusal and endoneurial capillaries was much lower than that in extrafusal capillaries, and HRP was never found outside the former vessels. In addition, HRP never completely penetrated through the spindle capsule from the extracellular into the periaxial space, although it was regularly found between the outer two or three layers of capsule cells. The results indicate that the permeability characteristics of the muscle spindle capillaries and capsule to the tracer protein HRP are very similar to those of capillaries in peripheral nerve.

Animals↗

PubMed1994

The somatostatin analogue octreotide protects against ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa.

Somatostatin 14 and various derivatives protect rat gastric mucosa against ethanol-induced lesions. Their mechanism of action is unknown. We investigated the effect of two somatostatin derivatives, octreotide and 5-(L)-citrullin-octreotide, on ethanol-induced hemorrhagic lesions, microcirculatory stasis and elevated vascular permeability in the rat stomach, with the goal to elucitate the pharmacological and microcirculatory mechanisms behind the gastroprotective effect. Radioligand studies revealed a high affinity of octreotide for the somatostatin receptor (IC50 = 5 x 10(-10) mol/l), in contrast to 5-(L)-citrullin-octreotide (IC50 = 3 x 10(-6) mol/l). This was in good agreement with the inhibition of growth hormone release from rat anterior pituitary cells (octreotide: IC50 = 1.2 x 10(-10) mol/l; 5-(L)-citrullin-octreotide: IC50 = 3 x 10(-6) mol/l). Intragastric administration of ethanol to rats resulted in lesions of the gastric mucosa affecting 18.9 +/- 3.1% of the area of the glandular stomach. Octreotide reduced the area to 6.4 +/- 1.7% (P < 0.05). The dose-response curve was bell-shaped. 5-(L)-citrullin-octreotide was totally devoid of any protective activity (dose range: 0.1 ng/kg to 0.1 mg/kg). We further investigated the effect of the two peptides on ethanol-induced microcirculatory stasis and elevated vascular permeability. Ethanol in a concentration of 50% induced an increase in microvascular permeability, measured by the extravasation of the tracer fluorescein-isothiocyanate-dextran (molecular weight 150,000). Pretreatment with octreotide (0.1 ng/kg s.c.) prevented stasis and reduced capillary permeability significantly. 5-(L)-citrullin-octreotide had no effect on ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

Stimulation of large-conductance Ca2+-activated K+ channels by Evans blue in cultured endothelial cells of human umbilical veins.

The effect of Evans blue (EB) on large-conductance Ca2+-activated K+ (BKCa) channels was investigated in cultured endothelial cells of human umbilical veins. In whole-cell configuration, EB (50 microM) reversibly increased the amplitude of K+ outward currents (IK). When the patch pipettes were filled with 10 mM EGTA, its stimulatory effect on IK was unaltered. Further application of EB in the presence of suramin, a blocker of P2-purinergic receptor, or AOPCP, an inhibitor of 5'-nucleotidase, still increased IK. However, charybdotoxin (100 nM) suppressed EB-induced increase in IK. In inside-out configuration, bath application of EB (50 microM) did not change single channel conductance but significantly increased the activity of BKCa channels. The EB-induced increase in the activity of BKCa channels was independent on internal Ca2+. EB (50 microM) shifted the activation curve of BKCa channels to less positive membrane potentials by approximately 20 mV. The change in the kinetic behavior of BKCa channels caused by EB in these cells is due to an increase in mean open time and a decrease in mean closed time. These results indicate that EB can stimulate the activity of BKCa channel in endothelial cells. This effect is unrelated to its blockade of P2-purinergic receptors or inhibition of 5'-nucleotidase. The direct stimulation of these ionic channels by EB may contribute to its effect on capillary permeability.

Adenosine Diphosphate↗

PubMed1982

Neurogenic pulmonary edema.

This report presents a patient who developed fulminant pulmonary edema as a complication of an acute subarachnoid hemorrhage. Hemodynamic evaluation revealed low-normal pulmonary arteriolar resistances. Endobronchial fluid was freely suctioned from the patient over a two-day period and had a colloid osmotic pressure and protein content equal to the patient's plasma throughout the entire course. These findings suggest that neurogenic pulmonary edema in this patient was related to increased capillary permeability and may occur independent of pulmonary hemodynamics.

Adult↗

PubMed1984

Heterogeneous models for blood-cerebrospinal fluid barrier permeability to serum proteins in normal and abnormal cerebrospinal fluid/serum protein concentration gradients.

Cerebrospinal fluid (CSF)/serum concentration gradients (Q) of individual proteins (albumin, IgG, alpha 2-macroglobulin) have been studied in controls and in patients in whom the lumbar CSF flow is altered (medullary compression) or the blood-CSF barrier (BCB) function impaired (acute idiopathic polyneuropathy and acute meningoencephalitis). The analysis of relationships among protein Q has been performed by total and multiple regressions and the actual BCB permeability to individual proteins has been interpreted according to the accepted theoretical porous or vesicular BCB models. The exponential Q-IgG vs. Q-albumin total regression, and the poor Q-alpha 2-macroglobulin vs. Q-albumin regression found in controls, together with the different multiple regressions among proteins and the high Q-IgG vs. Q-albumin partial regression coefficients found in medullary compression, acute idiopathic polyneuropathy and acute meningoencephalitis, indicated that different permeability mechanisms can be postulated. Heterogeneous, fairly independent permeability BCB mechanisms maintain the normal CSF/serum protein concentration gradient. Pinocytotic vesicles or pores of radius exceeding 1000-1500 A, probably located at the capillary endothelium, account for the main serum-derived CSF protein fraction(s) with large hydrodynamic radius (R). A more selective endothelial vesicular transport with a radius of 250 A transfers a negligible amount of protein from serum into CSF. Proteins with small R also enter the CSF through a set of selective pores of radius 120 A, probably at the level of the choroidal epithelium. Pinocytotic vesicles with a radius of 250 A and increased rate of formation induce the accumulation of proteins below an obstruction of lumbar CSF flow. An increased formation rate of vesicles with a radius of 450 A can explain the increased capillary permeability in nerve roots in acute idiopathic polyneuropathy. Loss of selectivity was the main feature of BCB in acute meningoencephalitis, and it seemed to be due to pores or vesicles with a radius larger than 1000-1500 A. The heterogeneity of BCB mechanisms must be taken into account when the intrathecal synthesis of a protein, also derived from serum (for example IgG), has to be measured.

Blood Proteins↗

PubMed1987

Transcapillary transport during secretion by the rabbit submandibular salivary gland.

Fluid exchange in the rabbit submandibular gland has been studied with a view to improving understanding of the mechanisms underlying transcapillary transport during salivation. Using maximally vasodilated glands perfused in vitro, we found that acetylcholine had no significant effect on either hydraulic conductance (filtration coefficient, Lp) or reflection coefficient to albumin (sigma alb) of the gland microvessels. In vivo, parasympathetic nerve stimulation increased blood flow 20-fold, interstitial fluid production (total fluid efflux - saliva flow) increased approximately 10-fold, while filtration fraction remained constant. At the same time, isogravimetric capillary pressure increased about six-fold. There are several possible explanations for these findings, and it is argued that they are likely to include capillary recruitment. Thus, during salivation, parasympathetic nerve stimulation does not lead to a change in capillary permeability as such, but rather produces a relaxation of resistance vessels and a fall in precapillary resistance, accompanied by an increase in available capillary surface area. This leads to a rise in capillary blood flow and pressure, which in turn increase fluid filtration. These changes are self-limiting due to the resulting dilution of interstitial protein and rise in interstitial pressure, but during salivation, since the secretion is pumped out of the interstitium, this fluid transport has no net effect on transcapillary gradients.

Acetylcholine↗

PubMed1997

Superoxide dismutase reduces islet microvascular injury induced by streptozotocin in the rat.

Intravenous administration of streptozotocin (STZ) leads to permanent diabetes mellitus in rats. We investigated the possible role of islet microcirculatory changes and free radical formation in this animal model. In vivo fluorescence microscopy was performed for 4 h after administration of STZ. Vascular permeability, capillary blood flow, and endothelial leukocyte adhesion were measured in endocrine and exocrine pancreatic tissue. The earliest microcirculatory event was an increase in vascular permeability in pancreatic islets, with a peak 1 h after STZ administration. The difference between islet and exocrine tissue light intensity was +15.8 +/- 5.6% at t = 60 min. Islet blood flow velocity significantly decreased after 3 h, whereas blood flow in the exocrine pancreas was not affected. Complete stasis of islet blood flow was observed only in rats receiving STZ. Neither increased leukocyte adhesion to islet vascular endothelium nor ischemia-reperfusion phenomena were observed. Prophylactic administration of the radical scavenger superoxide dismutase prevented STZ-induced damage to the islet microcirculation in the initial phase of this model. We conclude that STZ leads to severe microcirculatory disturbances within pancreatic islets in rats. Apparently, these changes are mediated at least in part by free oxygen radicals.

Animals↗

PubMed1980

Antiinflammatory principles of Aconitum roots.

The methanol extracts of Aconitum roots have shown inhibition of increased vascular permeability induced by acetic acid and of hind paw edema produced by carrageenin in mice. The extract of A. carmichaeli has been fractionated, monitored by the capillary permeability test, to yield the aconitines as active principles. The aconitines have inhibited the increased vascular permeability induced by acetic acid in mice peritoneal cavity and that induced by histamine in rat intradermal sites, and the hind paw edema formation induced by carrageenin n rats and mice at low doses. The benzoylaconines have exhibited inhibitory effects of the aforementioned acute inflammations but at higher doses. The aconitines have reduced the granulation tissue formation of the chorio-allantoic membrane of the chick embryo. On the other hand, the Aconitum alkaloids have elicited no effects on the ultraviolet erythema formation in guinea pigs at lower doses than the lethal ones and failed to show positive responses on the vascular permeability in the granuloma pouch and on adjuvant arthritis in rats at the doses employed.

Acetates↗

PubMedDate not supplied

Influence of a prostaglandin synthesis inhibitor and of thrombocytopenia on tumor blood flow and tumor vascular permeability. Experimental studies in the rat.

The intratumor distribution of vascular permeability in two transplantable rat tumors was studied by calculating tissue-plasma ratios of two intravenously injected labeled albumins with an interval of five hours between albumin injections. The data were calculated and presented as the capillary permeability surface area product (PS) in multiple tumor biopsies. Furthermore, the intratumor distribution of blood flow was studied by the intratumor uptake of intravenously injected 86Rb. The same parameters were also studied in normal striated muscle. Prolonged administration of a prostaglandin synthesis inhibitor, diclofenac-sodium (Voltaren) changed significantly the tumor blood flow towards higher values. A similar change was observed in animals with induced thrombocytopenia. Tumor PS values were increased by administration of diclofenac-sodium, but not by induced thrombocytopenia. The intratumor distribution of plasma volume, calculated from tissue-plasma values of albumin injected 5 minutes before the animals were killed, was not significantly changed as well as blood flow, plasma volume and PS in normal muscle. There was no significant correlation between separate tumor blood flow and PS values, while such a significant correlation was found in normal muscle. The observations made in this study suggest that a release of both prostaglandins and serotonin might be included in the regulation of tumor blood flow and vascular permeability.

Animals↗