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PubMed2003

Thyroid hormone modulates rabbit proximal straight tubule paracellular permeability.

Proximal straight tubules (PST) from both neonatal and hypothyroid adult rabbits have a lower rate of passive volume absorption when perfused with a high-chloride solution simulating late proximal tubular fluid than adult rabbit PST. We hypothesized that the maturational increase in serum thyroid hormone levels mediates the developmental changes in PST paracellular permeability. Neonatal tubules had lower chloride permeability, higher transepithelial resistance, but comparable mannitol permeability compared with adult PST. The present in vitro microperfusion study directly examined whether thyroid hormone affects passive solute flux and whether thyroid hormone could explain the developmental changes in PST paracellular permeability. Passive chloride transport was 62.1 +/- 4.5, 23.1 +/- 7.7, and 111.6 +/- 5.6 pmol.mm(-1).min(-1) in PST from euthyroid, hypothyroid, and hypothyroid animals that received thyroid treatment, respectively (control different from hypothyroid and thyroid treatment at P < 0.05). This was due to a thyroid hormone-mediated change in chloride permeability (P(Cl)). Mannitol permeability was 3.65 + 1.03, -0.19 + 0.72, and 3.60 + 1.12 x 10(-6) cm/s in PST from euthyroid animals, hypothyroid animals, and hypothyroid rabbits that received thyroid replacement, respectively (P < 0.05 hypothyroid vs. euthyroid and thyroid replacement). We demonstrate that PST from hypothyroid animals have a higher passive P(Na)/P(Cl) and P(HCO3)/P(Cl) than euthyroid controls. Finally, we examined whether these changes in permeability were paralleled by a change in PST paracellular resistance. Resistance was measured by current injection and cable analysis. The resistance in PST from hypothyroid rabbits was 6.3 +/- 0.8 Omega.cm(2), which was not different from control of 4.8 +/- 0.7 Omega.cm(2), or 7.0 +/- 0.7 Omega.cm(2) in hypothyroid animals that received thyroid replacement. Therefore, the maturational increase in thyroid hormone levels does not fully explain the developmental changes in the paracellular pathway.

Animals↗
PubMed1988

Hormone effects on NaCl permeability of rat inner medullary collecting duct.

It has been proposed that regulation of NaCl excretion occurs in part by hormonal effects on NaCl permeability in the inner medullary collecting duct (IMCD). We carried out experiments in isolated perfused terminal IMCDs to determine whether atrial natriuretic factor (ANF), vasopressin, or deoxycorticosterone (DOC) affects NaCl permeability. Apparent Cl- or Na+ permeabilities (PCl and PNa) were determined by measuring ion fluxes resulting from imposed electrochemical gradients. Transepithelial resistance (RT) was calculated from voltage deflections at the perfusion and collection ends of the tubule, which resulted from perfusion end current injection (cable analysis). ANF [rat ANF-(1-28), 100 nM in the peritubular bath] significantly decreased PCl from 2.20 to 1.84 x 10(-5) cm/s and did not alter PNa (1.11 to 1.18 x 10(-5) cm/s). ANF also decreased PCl in IMCDs from DOC-treated rats (1.14 to 0.98 x 10(-5) cm/s). Vasopressin (10 nM in the peritubular bath) did not affect PCl. RT averaged 39.3 omega.cm2 in IMCDs from control rats and was significantly increased to 62.3 omega.cm2 in tubules from DOC-treated rats. Neither ANF nor vasopressin significantly affected RT in either group. We conclude the following: 1) the results do not support the hypothesis that ANF causes natriuresis by increasing the NaCl permeability of the terminal IMCD. Instead, ANF significantly decreases the chloride permeability. 2) Vasopressin does not affect NaCl permeability. 3) Mineralocorticoid-induced antinatriuresis may be due in part to reduced NaCl permeability in the terminal IMCD.

Animals↗
PubMed1996

Permeability criteria for effective function of passive countercurrent multiplier.

The urine concentrating effect of the mammalian renal inner medulla has been attributed to countercurrent multiplication of a transepithelial osmotic difference arising from passive absorption of NaCl from thin ascending limbs of long loops of Henle. This study assesses, both mathematically and experimentally, whether the permeability criteria for effective function of this passive hypothesis are consistent with transport properties measured in long loops of Henle of chinchilla. Mathematical simulations incorporating loop of Henle transepithelial permeabilities idealized for the passive hypothesis generated a steep inner medullary osmotic gradient, confirming the fundamental feasibility of the passive hypothesis. However, when permeabilities measured in chinchilla were used, no inner medullary gradient was generated. A key parameter in the apparent failure of the passive hypothesis is the long-loop descending limb (LDL) urea permeability, which must be small to prevent significant transepithelial urea flux into inner medullary LDL. Consequently, experiments in isolated perfused thin LDL were conducted to determine whether the urea permeability may be lower under conditions more nearly resembling those in the inner medulla. LDL segments were dissected from 30-70% of the distance along the inner medullary axis of the chinchilla kidney. The factors tested were NaCl concentration (125-400 mM in perfusate and bath), urea concentration (5-500 mM in perfusate and bath), calcium concentration (2-8 mM in perfusate and bath), and protamine concentration (300 micrograms/ml in perfusate). None of these factors significantly altered the measured urea permeability, which exceeded 20 x 10(-5) cm/s for all conditions. Simulation results show that this moderately high urea permeability in LDL is an order of magnitude too high for effective operation of the passive countercurrent multiplier.

Animals↗
PubMed1996

Coupling of entry to exit by peritubular K+ permeability in a mathematical model of rat proximal tubule.

In the proximal tubule in vivo, glomerulotubular balance requires that tubule epithelial cells accommodate a twofold variation in Na+ reabsorption through the Na+/H+ exchanger of the luminal membrane. In a mathematical model of proximal tubule, in which permeability coefficients are fixed, doubling flux through the Na+/H+ antiporter produces a substantial increase in cell volume and cytosolic HCO3-. In this model, it is possible to vary peritubular K+ permeability with changes in luminal Na+ entry, so that cell volume is constrained to be constant. In these calculations, the model predicts that peritubular hyperpolarization and nearly constant cytosolic HCO3- will accompany increases in luminal Na+ entry. Realistic models of variable peritubular K+ permeability might include a functional dependence on flux through the Na(+)-K(+)-adenosinetriphosphatase, cytosolic pH, or cell volume. When K+ permeability is represented as a function of any of these variables, homeostatic control of cell volume and pH can be obtained over a physiological variation of Na+/H+ flux. However, when luminal Na+ entry is via Na(+)-glucose cotransport, volume homeostasis is best when peritubular K+ permeability depends on the rate of active Na+ transport. For any modulator of K+ permeability, realistic constraints on the value of this parameter suggest that peritubular K+ permeability is, by itself, not sufficient to maintain cell volume within narrow limits. Parallel activation of another exit pathway, such as peritubular Na(+)-3 HCO3- cotransport, may be required to achieve the necessary homeostasis.

Animals↗
PubMed1998

Disruption of guinea pig urinary bladder permeability barrier in noninfectious cystitis.

Although most cell membranes permit rapid flux of water, small nonelectrolytes, and ammonia, the apical membranes of bladder epithelial umbrella cells, which form the bladder permeability barrier, exhibit strikingly low permeabilities to these substances. In cystitis, disruption of the bladder permeability barrier may irritate the bladder wall layers underlying the epithelium, causing or exacerbating inflammation, and increasing urinary frequency, urgency, and bladder pain. To determine the effects of inflammation on the integrity of the permeability barrier, guinea pigs were sensitized with ovalbumin, and the bladders were exposed subsequently to antigen by instillation on the urinary side. Inflammation of the bladder wall markedly reduced transepithelial resistance of dissected epithelium mounted in Ussing chambers and increased water and urea permeabilities modestly at 2 h and more strikingly at 24 h after induction of the inflammation. Transmission and scanning electron microscopy of bladders at 30 min and 24 h after antigen exposure revealed disruption of tight junctions, denuding of patches of epithelium, and occasional loss of apical membrane architecture. These permeability and structural effects did not occur in nonsensitized animals in which the bladders were exposed to antigen and in sensitized animals exposed to saline vehicle rather than antigen. These results demonstrate that inflammation of the underlying muscle and lamina propria can disrupt the bladder permeability barrier by damaging tight junctions and apical membranes and causing sloughing of epithelial cells. Leakage of urinary constituents through the damaged epithelium may then exacerbate the inflammation in the underlying muscle layers.

Animals↗
PubMed1982

Lung inflation, lung solute permeability, and alveolar edema.

A series of experiments in anesthetized rabbits were conducted to determine whether hyperinflation of the lung alone could produce a protein-permeable lung epithelium and whether a protein-permeable lung epithelium allowed accumulation of liquid in the alveolar space. Some animals had their entire lungs subjected to distending pressures; others had only an area of the lung subjected to the high distending pressure. Alveolar liquid was measured by dilution of radioactive solutes upon instillation of saline into atelectatic lung, and protein permeability was determined by the loss of labeled albumin from the alveolar space over 40-60 min. Inflation of the entire lung at 40 cmH2O for 20 min increases air-space gas volume three- to fourfold, does not produce a protein-permeable epithelium, and does not result in accumulation of alveolar liquid. Distension of a small area of the lung by 40 cmH2O pressure for 20 min increases the gas volume 6- to 12-fold and produces a protein-permeable epithelium, but does not result in liquid accumulation in the alveoli. It is concluded that only very high distending volumes cause the lung epithelium to become permeable to protein and that a protein-permeable epithelium alone does not induce alveolar edema.

Animals↗
PubMed1992

Reversal of increased microvascular permeability associated with ischemia-reperfusion: role of cAMP.

Ischemia-reperfusion (IR) is a form of oxidant injury known to increase microvascular permeability in the lung. Agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) levels have been shown to have beneficial effects in several models of oxidant lung injury associated with increased microvascular permeability. We investigated the role of adenylate cyclase activation with isoproterenol (ISO) or forskolin (FSK) in reversing the increased microvascular permeability associated with IR. ISO or FSK administered after 45 min of ischemia and 46 min of reperfusion caused a reduction in the capillary filtration coefficient (Kfc) from 1.25 +/- 0.13 to 0.53 +/- 0.08 and 0.55 +/- 0.10 ml.min-1.cmH2O-1.100 g tissue-1, respectively, at 90 min of reperfusion. This reduction in Kfc was accompanied by a rise in perfusate cAMP levels from 16.5 +/- 4.9 and 31.2 +/- 11.9 pmol/ml at 45 min of reperfusion to 444.2 +/- 147.8 and 276.1 +/- 91.0 pmol/ml at 105 min of reperfusion in lungs treated with ISO or FSK, respectively, at 46 min of reperfusion. Dibutyryl cAMP (DBcAMP), a membrane-permeable cAMP analogue, mimicked the permeability effect by reducing Kfc to 0.67 +/- 0.15 at 90 min of reperfusion. Significant hemodynamic changes occurred but were small and cannot explain the observed effect on Kfc. Photomicrographs from lungs treated with ISO or FSK revealed a reversal of the morphological manifestations of increased microvascular permeability. We conclude that the increased microvascular permeability associated with IR can be reversed by ISO, FSK, and DBcAMP and that cAMP produced by the lung contributes to the observed reversal.

Animals↗
PubMed1992

Effects of cold on vascular permeability and edema formation in the isolated cat limb.

We investigated the effects of cold temperatures on microvascular protein permeability in the isolated constant-flow perfused cat hindlimb. The perfusates were 20% cat plasma-80% albumin-electrolyte solution (low-viscosity perfusate, approximately 1 cP) or whole blood (high-viscosity perfusate, approximately 4 cP). The time at low temperature (less than 10 degrees C) was less than 3 h (short term) or greater than 5 h (long term). Decreases in the solvent drag reflection coefficient (sigma f) indicated increases in permeability. The sigma f's were determined with the integral-mass balance method from measurement of changes in protein concentration and hematocrit induced by fluid filtration into the tissues. Short-term cold exposure did not increase permeability with either a low- or a high-viscosity perfusate, whereas long-term exposure with limb temperatures of approximately 5 degrees C significantly increased permeability when the perfusate was whole blood. In addition, we verified our previous prediction that flow had to be reduced to 6-8 ml.min-1.100 g-1 to avoid the hydrostatic edema caused by short-term perfusion with whole blood at approximately 5 degrees C. Also, we found that at approximately 3 degrees C histamine's permeability-increasing effect was totally abolished, whereas at approximately 20 degrees C this effect was partially inhibited. Hence, constant-flow perfusion at low temperature with whole blood can cause edema by a pressure-dependent mechanism, whereas long-term perfusion with this perfusate at low temperatures can cause a permeability increase that further compounds edema formation. Histamine is not responsible for this permeability increase.

Animals↗
PubMed1996

Thrombin increases fluid flux in isolated rat lungs by a hemodynamic and not a permeability mechanism.

Alpha-Thrombin increases endothelial protein permeability in vitro and induces weight gain in the isolated perfused lung. The objectives of this study were to determine whether thrombin increases endothelial permeability of the isolated perfused rat lung and whether a change in permeability or hemodynamics mediates the gain in lung weight. Endothelial protein permeability was assessed by regression analysis of 125I-labeled albumin clearance vs. fluid flux to determine the permeability-surface area product (PS) and the reflection coefficient (sigma). Thrombin (5 x 10(-8) or 5 x 10(-7) M) did not alter protein permeability from the control values of PS and sigma. Thrombin caused an overall increase in transvascular fluid flux, as depicted by a gain in lung weight. Pulmonary arterial and capillary pressures and arterial and venous resistances increased by 10 min after thrombin injection, and lung weight decreased due to arterial constriction. From 10 to 50 min, pressures and resistances decreased, but capillary pressure and venous resistance decreased to a lesser extent and, as a result, lung weight increased. Pretreatment with BQ-123, an endothelin-receptor antagonist, attenuated the sustained increases in pressures and resistances and the rate of lung weight gain. Indomethacin, a cyclooxygenase inhibitor, had no effect. These findings indicate that the increase in lung weight induced by thrombin results from an elevation of capillary pressure mediated, in part, by endothelin and is not due to an increase in endothelial protein permeability of the isolated perfused rat lung.

Animals↗
PubMedDate not supplied

Significance of nitric oxide and peroxynitrite in permeability changes of the retinal microvascular endothelial cell monolayer induced by vascular endothelial growth factor.

Reactive oxygen species (ROS) play an important role in signaling pathways stimulated by growth factors in vascular cells. We investigated whether vascular endothelial growth factor (VEGF), which is upregulated in diabetic retinopathy and atherosclerosis, is able to enhance production of ROS, and if so, whether ROS modulate endothelial permeability. ROS levels in bovine retinal microvascular endothelial cells (BMEC) were measured by the oxidation of 2', 7'-dichlorodihydrofluorescein (DCHF), and permeability was examined by monitoring the passage of albumin through BMEC monolayers. VEGF stimulated oxidation of DCHF in BMEC, an effect which was inhibited by superoxide dismutase (SOD) and the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), but not by D-NAME. Urate, a scavenger of peroxynitrite, attenuated the VEGF-induced oxidation of DCHF. VEGF elicited a significant increase in the macromolecule permeability of BMEC monolayers within 30 min. SOD did not modify the basal or the VEGF-stimulated hyperpermeability, but the combination of SOD and VEGF induced a transient reduction in permeability after 10 min. L-NAME, but not D-NAME, enhanced VEGF-induced hyperpermeability without affecting basal values. Urate did not modify the VEGF-induced changes in permeability. In conclusion, VEGF stimulates oxidation of DCHF, which most likely represents peroxynitrite formation, and induces an increase in permeability of BMEC monolayers. Activation of NO synthase seems to counteract this stimulatory effect of VEGF on endothelial permeability.

Animals↗
PubMed1989

Permeability of regenerating and atrophic choriocapillaris in the rabbit.

When rabbits receive intravenous injections of sodium iodate, large expanses of the retinal pigment epithelium are destroyed. The adjacent capillary bed, the choriocapillaris, atrophies in response to the loss of the pigment epithelium and then regenerates. This provides a model of the permeability of regenerating and atrophic choriocapillaris, which we studied using intravenously injected horseradish peroxidase and catalase. Regenerating capillaries were permeable to peroxidase but not catalase. The permeability to peroxidase was probably due to endothelial fenestrations, since catalase (which is larger than peroxidase and does not penetrate endothelial fenestrae) was retarded at interendothelial junctional complexes, indicating that they were intact. Atrophic choriocapillaries were impermeable to catalase but displayed a heterogeneous permeability to peroxidase. This was correlated with the presence or absence of fenestrae; capillary profiles lacking fenestrae retained peroxidase in their lumina, whereas if fenestrae were present the tracer penetrated into the pericapillary space. The observations indicate that: (1) the permeability of the regenerating choriocapillaris is qualitatively similar to the mature choriocapillaris, and (2) the atrophic choriocapillaris undergoes changes in permeability that are primarily correlated with the loss of endothelial fenestrae. The observations provide a functional correlate - change in permeability - for structural changes in choriocapillaris endothelium (thickening, loss of fenestrae) in response to destruction of the retinal pigment epithelium, which has been postulated to exert a trophic effect on these capillaries.

Animals↗
PubMed1987

Effects of antigen challenge on intestinal permeability and morphology in rats immunized with gliadin or ovalbumin.

In this study we have investigated the possible effects of a local immune response on the intestinal permeability and morphology in rats. The animals were immunized subcutaneously by small doses of gliadin or ovalbumin. Immunization with gliadin led to small but significantly increased levels of IgA and IgM antibodies, similar to those reported for patients with coeliac disease. Immunization with ovalbumin gave significantly increased antibody levels of IgE, IgG, IgA and IgM. Subsequent antigen provocations by oral administration of gliadin (1 mg), together with fluorescein isothiocyanate-labelled dextran (molecular weight 3,000 daltons) as permeability marker, resulted in an increased intestinal permeability for this marker. This alteration of the intestinal permeability was qualitatively similar to that previously reported for patients with coeliac disease. Antigen provocation with ovalbumin caused a decreased permeability for both dextran and different-sized polyethylene glycols, but first at a dose of 40 mg. Direct antigen administration (gliadin or ovalbumin) into a ligated part of the ileum gave qualitatively similar but less pronounced permeability changes when compared with the effects obtained after oral administration of the respective antigen. However, neither gliadin nor ovalbumin challenge led to any ultrastructural changes of the intestinal wall. In summary, we have been successful in inducing specific antibody responses towards gliadin in rats and increased intestinal permeability upon gliadin provocation without any coexisting morphological alterations.

Animals↗
PubMed1992

Effect of oxymetazoline nose drops on vascular permeability of the nasal mucosa in the rabbit after provocation with leukotriene B4.

The effects of oxymetazoline nose drops on the vascular permeability of the nasal mucosa in a provoked inflammatory reaction was studied in anesthetized rabbits. Vascular permeability (125I-albumin) was 53% higher in the leukotriene B4-provoked nostril (LTB4) compared with the vehicle-treated contralateral nostril (p < 0.05). The amount of secretions was, however, not different from the vehicle-treated side. The LTB4-induced increase in permeability was decreased by 22% when oxymetazoline was introduced (p < 0.05), and the amount of secretions was reduced by 22% (p < 0.01). The effect of oxymetazoline on the vascular permeability of the nasal mucosa can be attributed to a vascular constriction (decrease in blood flow) and/or a change in the permeability characteristics. The LTB4-induced increase in vascular permeability was not attenuated by the monoclonal antibody IB4 directed against the neutrophil adhesion complex CD11/CD18. The latter suggests that LTB4-induced vascular permeability does not require CD18-mediated neutrophil adherence in the nasal mucosa.

Administration, Intranasal↗
PubMed2003

Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability.

BACKGROUND: Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) induces both angiogenesis and vascular permeability. Although its angiogenic activity has been well characterized, the signaling pathways of VEGF-induced permeability remain poorly understood. METHODS AND RESULTS: Using the mouse corneal micropocket assay, Miles assay, and a combination of cytochemical, electron microscopic, and biochemical assays, we demonstrate that VEGF-induced vascular leakage partly can be separated from its angiogenic activity. VEGF but not FGF-2 induced capillaries with a highly fenestrated endothelium, a feature linked with increased vascular permeability. A cell-permeable Rac antagonist (TAT-RacN17) converted VEGF-induced, leaky vascular plexuses into well-defined vascular networks. In addition, this Rac mutant blocked formation of VEGF-induced endothelial fenestrations and vascular permeability but only partially inhibited angiogenesis. Studies on endothelial cell cultures further revealed that VEGF stimulated phosphorylation of VEGF receptor-2 (VEGFR-2), leading to activation of Rac as well as increased phosphorylation of phospholipase Cgamma (PLCgamma), protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), and extracellular regulated kinase (Erk1/2). We further found that phosphatidylinositol-3-OH kinase (PI3K) acted upstream of Rac and Akt-eNOS in VEGF/VEGFR-2 signaling. CONCLUSIONS: Our findings indicate that the small GTP-binding protein Rac is a key component in mediation of VEGF-induced vascular permeability but less so in neovascularization. This may have conceptual implications for applying Rac antagonists in treatment and prevention of VEGF-induced vascular leakage and edema in connection with ischemic disorders.

Animals↗
PubMed1999

Calcium antagonists ameliorate ischemia-induced endothelial cell permeability by inhibiting protein kinase C.

BACKGROUND: Dihydropyridines block calcium channels; however, they also influence endothelial cells, which do not express calcium channels. We tested the hypothesis that nifedipine can prevent ischemia-induced endothelial permeability increases by inhibiting protein kinase C (PKC) in cultured porcine endothelial cells. METHODS AND RESULTS: Ischemia was induced by potassium cyanide/deoxyglucose, and permeability was measured by albumin flux. Ion channels were characterized by patch clamp. [Ca2+]i was measured by fura 2. PKC activity was measured by substrate phosphorylation after cell fractionation. PKC isoforms were assessed by Western blot and confocal microscopy. Nifedipine prevented the ischemia-induced increase in permeability in a dose-dependent manner. Ischemia increased [Ca2+]i, which was not affected by nifedipine. Instead, ischemia-induced PKC translocation was prevented by nifedipine. Phorbol ester also increased endothelial cell permeability, which was dose dependently inhibited by nifedipine. The effects of non-calcium-channel-binding dihydropyridine derivatives were similar. Analysis of the PKC isoforms showed that nifedipine prevented ischemia-induced translocation of PKC-alpha and PKC-zeta. Specific inhibition of PKC isoforms with antisense oligodeoxynucleotides demonstrated a major role for PKC-alpha. CONCLUSIONS: Nifedipine exerts a direct effect on endothelial cell permeability that is independent of calcium channels. The inhibition of ischemia-induced permeability by nifedipine seems to be mediated primarily by PKC-alpha inhibition. Anti-ischemic effects of dihydropyridine calcium antagonists could be due in part to their effects on endothelial cell permeability.

Animals↗
PubMed2003

Isoprenylcysteine carboxyl methyltransferase modulates endothelial monolayer permeability: involvement of RhoA carboxyl methylation.

RhoA and Rac1 regulate formation of stress fibers and intercellular junctions, thus modulating endothelial monolayer permeability. Posttranslational modifications of RhoA and Rac1 regulate enzyme activity and subcellular localization, resulting in altered cellular function. The role of RhoA and Rac1 carboxyl methylation in modulating endothelial monolayer permeability is not known. In this study, we found that inhibition of isoprenylcysteine-O-carboxyl methyltransferase (ICMT) with adenosine plus homocysteine or N-acetyl-S-geranylgeranyl-l-cysteine decreased RhoA carboxyl methylation, RhoA activity, and endothelial monolayer permeability, suggesting that RhoA carboxyl methylation may play a role in the ICMT-modulated monolayer permeability. Similar studies showed no effect of ICMT inhibition on Rac1 carboxyl methylation or localization. Bovine pulmonary artery endothelial cells (PAECs) stably overexpressing ICMT-GFP cDNA were established to determine if increased ICMT expression could alter RhoA or Rac1 carboxyl methylation, activation, and endothelial monolayer permeability. PAECs stably overexpressing ICMT demonstrated increased RhoA carboxyl methylation, membrane-bound RhoA, and RhoA activity. Additionally, PAECs stably overexpressing ICMT had diminished VE-cadherin and beta-catenin at intercellular junctions, with resultant intercellular gap formation, as well as enhanced monolayer permeability. These effects were blunted by adenosine plus homocysteine and by inhibition of RhoA, but not by inhibition of Rac1. These results indicate that ICMT modulates endothelial monolayer permeability by altering RhoA carboxyl methylation and activation, thus changing the organization of intercellular junctions. Therefore, carboxyl methylation of RhoA may modulate endothelial barrier function.

Adenosine↗
PubMed1985

The role of oxygen-derived free radicals in ischemia-induced increases in canine skeletal muscle vascular permeability.

Previous studies indicate that vascular permeability is increased in skeletal muscle subjected to 4 hours of inflow occlusion. However, the mechanism(s) underlying the increase in permeability are unknown. The aim of this study was to assess the role of oxygen-derived free radicals and histamine as putative mediators of the increased permeability in skeletal muscle subjected to 4 hours of inflow occlusion. The osmotic reflection coefficient for total plasma proteins and isogravimetric capillary pressure were estimated in canine gracilis muscle for the following conditions: control, ischemia, and ischemia plus pretreatment with allopurinol (a xanthine oxidase inhibitor), catalase (a peroxidase that reduces hydrogen peroxide to water and molecular oxygen), superoxide dismutase (a superoxide anion scavenger), dimethyl sulfoxide (a hydroxyl radical scavenger), diphenhydramine (a histamine H1-receptor blocker), or cimetidine (a histamine H2-receptor blocker). Ischemia, followed by reperfusion, significantly reduced the reflection coefficient from 0.94 +/- 0.02 to 0.64 +/- 0.02 and isogravimetric capillary pressure from 13.8 +/- 1.0 mm Hg to 6.9 +/- 0.4 mmHg, indicating a dramatic increase in microvascular permeability. Prior treatment with diphenhydramine or cimetidine did not significantly alter the permeability increase induced by ischemia. However, pretreatment with allopurinol, catalase, superoxide dismutase, or dimethylsulfoxide did significantly attenuate the increase in vascular permeability. The results of this study indicate that oxygen radicals are primarily responsible for the increased vascular permeability produced by ischemia-reperfusion, that the hydroxyl radical may represent the primary damaging radical, and that xanthine oxidase may represent the primary source of oxygen-derived free radicals in ischemic skeletal muscle.

Allopurinol↗
PubMed1992

Measurement of endothelial permeability to 125I-low density lipoproteins in rabbit arteries by use of en face preparations.

A procedure of en face quantitative autoradiography of the endothelium (Hautchen preparations) was developed to examine regional variations in 125I-low density lipoprotein (125I-LDL) permeability in the arterial wall in vivo. Endothelial preparations from fixed arterial tissue and calibration standards consisting of known concentrations of 125I-albumin were dipped in nuclear emulsion, exposed for 1-3 months, developed, and stained with hematoxylin. Digital image analysis was used to analyze dark-field images of autoradiographs. Background grain densities on cold endothelial preparations were 30-100% higher than on glass, but the variability in grain densities on the two different surfaces was similar. Regression slopes of grain density versus concentration for calibration standards were the same for sections placed on cold tissue or glass. For 1-5-microns-thick calibration standards of the same concentration, the grain density was proportional to the total amount of radioactivity per unit area. The results indicated that errors arising from nonuniformities in preparation thickness were minimal, and permeabilities and intimal concentrations could be determined. Rabbits were killed 10 minutes after injection of 125I-LDL, and endothelial preparations were made. For regions of uniformly low grain density in the rabbit aorta, the 125I-LDL permeability was 1.9 +/- 0.8 x 10(-8) cm/sec, and the effective diffusion coefficient was 5.4 +/- 3.1 x 10(-10) cm2/sec. Errors in the estimated permeability arising from nonuniformities in tissue thickness were the same as the reported experimental variability. Analysis of elevated regions of permeability suggested that 125I-LDL was binding to the extracellular matrix. Approximately 25% of the sites of elevated grain density were associated with mitotic endothelial cells, and such regions had higher permeabilities than sites associated with nonmitotic cells. Around intercostal arteries, sites of highest permeability were distal and lateral to the vessels and occurred where lesions first develop in hypercholesterolemic rabbits.

Animals↗