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PubMed1982

A protease-like permeability factor in guinea pig skin: immunologic identity with plasma Hageman factor.

Vascular permeability enhancement activity of the protease-like permeability factor derived from guinea pig skin and of active guinea pig Hageman factor (beta HFa) were both inhibited by anti-guinea pig Hageman factor rabbit F(ab')2 antibody. The permeability activity of both factors was also absorbed on anti-Hageman factor F(ab')2-Sepharose beads. The latent form of the permeability factor derived from skin extracts produced a single immunoprecipitation line with anti-Hageman factor and gave a reaction of identity with a precipitation band developing between purified Hageman factor and anti-Hageman factor. The latent permeability factor in the fraction corrected the clotting activity of Hageman-factor-deficient human plasma. The clotting activity was also blocked by anti-Hageman factor F(ab')2 antibody. From these results, it was concluded that the skin permeability factor was immunologically and functionally indistinguishable from Hageman factor of plasma. Extracts were obtained from skin of guinea pigs given intravenous injections of 125I-guinea pig Hageman factor immediately before sacrifice to calculate the amount of Hageman factor in the extravascular tissue space of the skin. The pseudoglobulin fractions of the extracts containing a concentration of Hageman factor of approximately 9 microgram of Hageman factor per gram of skin. This was determined both by immunologic means and procoagulant activity. Only 4% of the Hageman factor in the extract was obtained from the intravascular plasma volume of the skin.

Animals↗
PubMedDate not supplied

[Study of sarcoplasmic reticulum membrane permeability using potential-sensitive fluorescent probes].

A new method is proposed for quantitative studies of SR membrane permeability. It involves measuring to diffusion potentials, arising at salt concentration gradient on the SR membrane due to its anion and cation permeability differences. Visualization of processes of negative chloride potential arising in adding MeCl2 and its further dissipation was realized with diS-C3-(5). A/23187 and X-537A in small concentrations reduce the amplitude and the length of fluorescent signal, while in strong concentrations they fully prevent it. Dissipation kinetics of chloride potential caused by the SR membrane permeability for Me2+ is used for quantitative analysis of this permeability. It is shown that the parameter tau 1/2 corresponds to the moment of time when the inside concentration of Me2+ becomes equal to the geometric average of the initial concentrations of this ion. The relationship between tau 1/2 and the concentrations of the added MeCl2 and the penetration ion (K+) and temperature were studied. It was shown that the membrane permeability gain with increasing MeCl2 concentration is due to accelerating action of the membrane potential. A laser two-wave, two-beam installation was described which allows to study SR membrane permeability with potential-sensitive probe fluorescence and light scattering on the same sample. Correlation between the signals obtained simultaneously with these independent methods was shown.

Animals↗
PubMed1995

High glucose modulates albumin permeability across glomerular endothelial cells via a protein kinase C-dependent mechanism.

To investigate the mechanism of glomerular endothelial response to high glucose, an in vitro model of the glomerular endothelial barrier was established in which transfer of fluorescein-labeled albumin across confluent monolayers of immortalized bovine glomerular endothelial cells (GEN) grown on polycarbonate membranes was measured. We first examined the effects of increased concentrations of D-glucose on albumin permeability across GEN monolayers and further investigated the role of protein kinase C (PKC) in the regulation of glucose-induced changes in endothelial barrier function. Incubation with 30 mM D-glucose increased albumin permeability more than those with 10 mM D-glucose. Albumin permeability incubated with 10 mM D-glucose plus 20 mM mannitol was not significantly different from those with 10 mM D-glucose, indicating that the increase in albumin permeability induced by 30 mM D-glucose was not due to high osmolar stimuli. A protein kinase C (PKC) inhibitor, H-7 (25 microM) significantly reduced the permeability-increasing effects of D-glucose. Lactate dehydrogenase release from endothelial cells was not significantly increased above baseline after incubation with 10 mM or 30 mM D-glucose. These results suggest that elevated concentrations of glucose activates PKC, resulting in an increase in albumin permeability across GEN.

Animals↗
PubMed1995

Effect of the lipoxygenase inhibitor N-hydroxy-N-(6-methoxy-3,4-dihydro-2-naphthylmethyl)urea on bronchoconstriction and lung vascular permeability in anaphylactic guinea pigs.

Narrowing of the airway lumen as a result of plasma exudation could augment airflow obstruction after allergen-induced bronchoconstriction. Because leukotrienes are putative mediators of bronchial asthma, the effects of a lipoxygenase inhibitor, VZ564 (N-hydroxy-N-(6-methoxy-3,4-dihydro-2- naphthylmethyl) urea. CAS 147495-99-6), on increased pulmonary permeability and bronchoconstriction during anaphylactic reaction were studied in guinea pigs and compared to the effects of the phosphodiesterase inhibitor theophylline. An anaphylactic reaction was induced by ovalbumin challenge (0.2 mg/kg i.v.) in passively sensitized and antihistamine (mepyramine)-pretreated guinea pigs; bronchoconstriction was measured as increased intratracheal pressure; lung vascular permeability was evaluated as extravasation of Evans blue dye up to 10 min after antigenic challenge. Ovalbumin challenge induced an increase in intratracheal pressure by 31 +/- 3 mmHg; the pulmonary permeability index was higher in ovalbumin-challenged versus saline (sham)-challenged guinea pigs (1.49 +/- 0.17 vs 0.56 +/- 0.04, p < 0.05). VZ564 and theophylline dose-dependently reduced increased pulmonary permeability and bronchoconstriction. VZ564 (10 and 46.4 mg/kg p.o., given 1 h before ovalbumin challenge) inhibited increased lung permeability by 42% and 95% and reduced bronchoconstriction by 61% at the higher dose. Theophylline (1 and 10 mg/kg i.v., given 10 min before ovalbumin challenge) diminished increased pulmonary permeability by 88% and reduced bronchoconstriction by 63% at the higher dose. In conclusion, the novel lipoxygenase inhibitor VZ564 inhibits after oral application important symptoms of asthma, namely bronchoconstriction and alveolar exudation of plasma in anaphylactic guinea pigs. The acute effects of VZ564 in this experimental model are comparable with the effects of the well known antiasthmatic substance theophylline.

Anaphylaxis↗
PubMedDate not supplied

The effect of dentin depth on the permeability and ultrastructure of primary molars.

The purpose of this study was to measure the permeability of primary molar and permanent premolar dentin at various thicknesses from the pulp and to correlate permeability with the tubule density and diameter of dentin using SEM. The data were examined for statistically significant differences using two-way analysis of variance, multiple comparison Scheffe, and regression analysis. The permeability of all teeth increased with decreasing dentin thickness. The removal of the smear layer resulted in a significant increase in the permeability. However, the permeability of the dentin in premolars was significantly higher than that in the primary molars. The density and diameter of the dentinal tubular in primary molars were lower than the values reported for permanent teeth and may account for the lower permeability of the primary molars.

Adolescent↗
PubMed1993

Permeability of the blood-retinal barrier and the blood-aqueous barrier in type I diabetes without diabetic retinopathy: simultaneous evaluation with fluorophotometry.

For the evaluation of a possible malfunction of the blood-retinal barrier (BRB) and the blood-aqueous barrier (BAB) in type I diabetes without manifest angiopathy after i.v. injection of sodium fluorescein, the permeability of the BRB (P) and the permeability coefficient of the BAB [P(a)] were simultaneously determined by fluorophotometry in 34 eyes of 34 type-I diabetics [hemoglobin (Hb)A1c = 6.6% +/- 0.9%] without retinopathy whose age ranged from 19 to 38 years (mean, 30.5 +/- 5 years); the diabetes duration was between 5 and 18 years. Fluorescein angiography was performed to exclude nonperfused areas. In all, 34 eyes of 34 healthy volunteers whose age ranged between 23 and 34 years (mean, 28.5 +/- 3.3 years) served as controls; in this group, fluorophotometry was performed twice to evaluate reproducibility. The mean BAB permeability coefficient in diabetics [P(a) = 5.3 +/- 1.8 x 10(-4)/min] was significantly increased (P = 0.00003) as compared with control values [P(a) = 3.7 +/- 0.7 x 10(-4)/min]; BRB permeability in diabetics (P = 3.2 +/- 1.4 x 10(-7) cm/s) was raised, with this elevation being of lower significance (P = 0.019; controls, P = 2.6 +/- 0.7 x 10(-7) cm/s). We found a decrease in BRB permeability depending on diabetes duration (r = -0.15; P = 0.007) that was not significant in the BAB (r = -0.1; P = 0.24). No correlation was found to exist between permeability and hemoglobin (Hb)A1c values either in the BAB or in the BRB. The reproducibility in controls was 9% in BRB determinations and 12% in BAB measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Effect of leukocyte adhesion and microvascular permeability on capillary perfusion during ischemia-reperfusion injury in hamster cheek pouch.

The role of leukocyte sticking and permeability changes in the variation of perfused capillaries induced by ischemia reperfusion was studied in the hamster cheek pouch microcirculation. The drugs utilized were the antiperoxidative agents allopurinol, the calcium antagonists verapamil and diltiazem, and phenidone and adenosine, which inhibit leukotriene formation as well as leukocyte adhesion to the endothelium. The microvasculature was visualized by a fluorescence technique. Ischemia was induced by clamping the cheek pouch for 30 minutes followed by 30 minutes of reperfusion. The increase in permeability, the perfused capillary length and the number of adhering leukocytes to venular vessel wall were measured. Ischemia and reperfusion were associated with increased permeability, increased number of leukocytes sticking to the venular wall, and decreased number of functional capillaries. Microvascular injury evidenced by increased permeability was apparent in the first 5 min of ischemia. All the drugs decreased the number of leukocytes sticking to the venular wall; allopurinol, verapamil and adenosine reduced the increase in permeability, whereas phenidone and diltiazem were effective only during ischemia. In addition verapamil and adenosine preserved capillary blood flow during reperfusion. In conclusion, leukocyte sticking is correlated with increased microvascular permeability, but not with decreased perfusion of the capillary bed. These data suggest that leukocytes did not play a prominent role in the reduction of functional capillaries at the end of reperfusion.

Adenosine↗
PubMed1993

Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition.

Cyclosporin A (CyA) and L-carnitine (LC) prevented the killing of cultured hepatocytes by anoxia and rotenone but not by cyanide. Neither CyA nor LC affected the rate or extent of the loss of the mitochondrial membrane potential or the rate or extent of the depletion of ATP. Atractyloside blocked the ability of both CyA and LC to protect, and D-carnitine antagonized the effect of LC but not that of CyA. Cell killing by cyanide was prevented when the phospholipase A2 inhibitor butacaine was added together with CyA. Butacaine by itself had no effect on cell killing. In a swelling assay with isolated rat liver mitochondria having a low calcium content, phenylarsine oxide or palmitoyl-CoA induced the inner membrane permeability transition when electron transport was inhibited by rotenone or cyanide. CyA prevented the permeability transition with rotenone but not with cyanide, and atractyloside reversed the effect of CyA. LC prevented the permeability transition occurring with palmitoyl-CoA plus rotenone but not with palmitoyl-CoA plus cyanide. Atractyloside and D-carnitine antagonized the protective effect of LC. Inhibition of the cyanide-dependent permeability transition in isolated liver mitochondria required the presence of both CyA and butacaine. These data document the close correlation between the effect of CyA and LC on the response of cultured hepatocytes to inhibition of mitochondrial electron transport and their ability to prevent the permeability transition in isolated mitochondria. It is concluded that the ability of CyA and LC to protect cultured hepatocytes is a consequence of their ability to prevent the mitochondrial permeability transition, indicating that this event is likely to be causally linked to the genesis of irreversible injury. Thus, cell death with anoxia or inhibitors of electron transport is related to a mitochondrial alteration by a mechanism that is independent of the maintenance of a membrane potential or cellular stores of ATP.

4-Aminobenzoic Acid↗
PubMed1993

[Assessment of pulmonary aerosol deposition and epithelial permeability in 99mTc-DTPA inhalation scintigram].

The degree of lung injury in bronchiolo-alveolar lesions may be quantitated from the pulmonary epithelial permeability estimated by 99mTc-DTPA (diethylene triamine penta acetate) aerosol inhalation scintigram. However, significant aerosol deposition sometimes occurs in the central airways and obscures the permeability change in the lung periphery. The radioaerosol deposition pattern and its effect on assessing the pulmonary epithelial permeability was studied. 99mTc-DTPA aerosol scintigraphy was performed in 47 patients with pulmonary fibrosis (PF), 12 patients with chronic obstructive pulmonary diseases (COPD), and 27 non-smoking and 17 smoking healthy volunteers. The scintigraphic images of the lungs were classified into 4 grades, 0; homogeneous distribution, 1; patchy distribution, 2; hot spots with partial defect, and 3; hot spots with little deposition in the lung field. The rate constant was used as a parameter for the permeability. The smokers and patients with PF showed increased kep values of 2.36 +/- 1.21%/min (mean +/- SD) and 2.49 +/- 1.29%/min as compared with the nonsmokers with 0.94 +/- 0.27%/min, respectively. The nonsmokers, smokers and 36 patients with PF were classified as deposition grade 0 or 1, suggesting good aerosol penetration to the lung periphery. All patients with COPD showed either grade 2 or 3 deposition. Aerosol deposition in the central airways can cause underestimation of the permeability because of the thicker lining layer in the bronchus than in the alveolus. In conclusion, the aerosol deposition pattern should be analyzed when the method is applied clinically to assess the permeability of the bronchiolo-alveolar epithelium.

Adult↗
PubMed1993

[Increase in capillary permeability induced by endotoxin: protection with antioxidants and glutathione].

Endotoxin administration increases capillary permeability in experimental animals and this is one of the most relevant events in the pathophysiology of endotoxin shock; the aim of the present experiment was to demonstrate that the action of endotoxin on capillary permeability is due to oxygen-free radicals generation. Experiments were performed on the mesocecum of male Wistar rats; fluorescent labeled bovine albumin (FITC-BSA) was injected intra-arterially to evaluate the capillary permeability; the mesocecum microcirculation was observed by fluorescent light. Permeability was quantified by changes in the number of leaky sites at 10 minute intervals for an hour. The effects of Endotoxin (DIFCO 0111:B4, 30 mg/kg i.a.) were assessed in rats receiving 1) saline, 2) reduced glutathione (250 or 500 mg/kg i.p.), 3) three different nitrones (PBN, DMPO, POBN) (6.25 mg/kg i.p.) whose action is to "trap" oxygen radicals. Capillary permeability largely increased in a few minutes in control rats but it was quite unaffected in rats receiving glutathione or nitrones. As a conclusion the increased capillary permeability observed after endotoxin injection in rats may be due to an oxygen-radicals generation.

Animals↗
PubMed1993

Coronary microvascular fluid flux and permeability: influence of angiotensin II, aldosterone, and acute arterial hypertension.

Vascular permeability of the coronary and mesenteric circulation is increased in association with the arterial hypertension that accompanies either endogenous activation of the renin-angiotensin-aldosterone system (RAAS) or exogenous administration of angiotensin II (AII). Whether this occurs as a result of increased intravascular pressure or of elevations in plasma concentrations of AII or aldosterone (ALDO) (or both) is unclear. This acute study of filtration-independent coronary fluid exchange and macromolecular permeability was undertaken to address these issues in open-chest, anesthetized dogs. The influence of arterial hypertension, with or without associated elevations in plasma AII or ALDO (or both), on coronary permeability was examined by monitoring the response in cardiac lymph flow, protein concentration, and capillary and intramural coronary artery structure. Experimental groups received a 90-minute intravenous infusion of either AII (n = 8), methoxamine (MX; n = 7), or ALDO plus MX (n = 5) in equipotent doses that raised arterial pressure to comparable levels. When we compared these animals with normotensive, instrumented controls (n = 5), we found that (1) lymph flow was a function of arterial and microvascular pressures in each group; (2) increased protein permeability, myocardial edema, extravasated red cells, and infused colloidal carbon were found in both ventricles with AII, together with endothelial discontinuities and enhanced abluminal capillary endothelial vesicle formation, when plasma ALDO had risen significantly in response to AII; and (3) macromolecular permeability was no different from that in controls after MX or ALDO plus MX. Based on this short-term study of acute arterial hypertension, we would conclude that acute elevations in microvascular pressure increase fluid flux, whereas increased circulating effector hormones of the RAAS, not plasma ALDO or hypertension alone, alter coronary microvascular structure and permeability to macromolecules Responsible mechanisms remain to be defined.

Aldosterone↗
PubMed1995

Small bowel permeability--a variable effect of NSAIDS.

The baseline permeability of small bowel in 57 healthy volunteers was assessed by measuring the mannitol and chromium-EDTA recovery in a 5-hour urine collection after ingestion of a drink containing a mixture of 1 g of mannitol and 3.7 MBq of 51Cr-EDTA. Subjects were treated with medication for 1 week followed by permeability studies as described above. The regimens used were diclofenac sodium (Voltaren) 50 mg po tid (21 subjects), Voltaren SR 75 mg bid for 1 week (34 subjects), indomethacin 50 mg tid (10 subjects), and tenoxicam (Mobiflex) 20 mg daily (13 subjects). There was no significant difference between the mannitol recoveries at baseline or after any of the drugs. The permeability was clearly increased by indomethacin and by Voltaren SR. Conventional-release Voltaren increased permeability, but the results were not significantly above baseline. Mobiflex had no influence on the measured permeability. Our results suggest that the SR preparation of diclofenac has a more pronounced effect than regular diclofenac sodium; thus different NSAIDs and different preparations of the same NSAID may have different effects on small bowel permeability.

Adult↗
PubMed1996

Effect of tumor necrosis factor alpha on rabbit corneal endothelial permeability.

PURPOSE: Tumor necrosis factor alpha (TNF alpha) is present in the iris and the lacrimal gland, and its concentration is increased during inflammation and after corneal wounding. Although TNF alpha has been shown to increase keratocyte and corneal epithelial interleukin production, no definitive effects of TNF alpha on corneal endothelial cells have been reported. TNF alpha has been shown to disrupt barrier function in vascular endothelial monolayers through f-actin depolymerization. A reduction in intracellular cyclic adenosine monophosphate (cAMP) concentration may play a role in this response. This study was designed to examine the role and signal transduction mechanisms of TNF alpha modulation of endothelial permeability in the cornea. In addition, it is the first examination of the effects of TNF alpha on the barrier function of a noncultured cell monolayer. METHODS: Rabbit corneal endothelial superfusions were performed under an in vitro specular microscope. Corneas were processed for permeability measurements or f-actin staining. RESULTS: TNF alpha superfused corneas had significantly higher permeabilities than controls. f-actin staining revealed that TNF alpha superfusion disrupted f-actin filaments when compared to controls. Corneas superfused with the f-actin stabilizing agent phallacidin had significantly lower permeabilities than TNF alpha superfused pairs. Permeabilities of corneas superfused with TNF alpha plus 8-bromo-cAMP (0.01 to 3 mM) were significantly lower than TNF alpha superfused pairs at all concentrations, although only significantly lower at the 0.1 mM cAMP concentration. CONCLUSIONS: TNF alpha causes an increase in corneal endothelial permeability, and this increase is mediated by disruption of f-actin filaments; cAMP appears to be involved in this response.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMedDate not supplied

Effects of novel and conventional anti-cancer agents on human endothelial permeability: influence of tumour secreted factors.

A number of anti-cancer agents have been implicated in vascular toxicity. The effects have been attributed to direct drug toxicity towards endothelium. Little attention has been focussed on the interaction between anticancer drugs, endothelial cells and tumour secreted factors. It is well known that tumours can secrete factors such as vascular permeability factor which do affect endothelial cells and could alter their response to the vascular effects of anticancer drugs. In the present study, we have examined, in vitro, the direct effects of vinblastine (VBL), 5-fluorouracil (5-FU), melphalan (L-PAM) and the novel tubulin inhibitor combretastatin A-1 (CBS) on endothelial permeability under normal and tumour simulated conditions. Monolayers of human umbilical vein endothelial cells (HUVEC) grown on membrane filters were incubated in drug in normal growth medium or medium conditioned by the human melanoma cell line, RPMI-7951 (TCM). VBL caused a rapid increase in permeability during the first 20 minutes, which was maintained for the duration of the experiment (120 minutes). The effect was not altered by TCM or restored to control levels when VBL was replaced by drug-free medium. Similarly, CBS caused a rapid increase in permeability; however, in contrast to VBL, this increase was enhanced by TCM. The changes induced by VBL and CBS were accompanied by contraction of the endothelial F-actin cytoskeleton. Neither L-PAM nor 5-FU altered the permeability of HUVEC monolayers. This study demonstrates that certain anti-cancer agents have a direct effect on endothelial cells, leading to an increase in the permeability of endothelial monolayers. Both VBL and CBS have vascular components in their mode of action which may lead to vascular collapse and tumour necrosis.

Antineoplastic Agents↗
PubMed1998

Cyclic GMP-specific phosphodiesterase inhibition and intracarotid bradykinin infusion enhances permeability into brain tumors.

Intracarotid infusion of bradykinin selectively increases the delivery of compounds into brain tumors. This study sought to determine the role of cyclic GMP in increased permeability across the blood-tumor barrier (BTB) after infusion of bradykinin. In permeability studies, 186 Wistar rats with RG2 gliomas and C6 gliomas were used. Transport across the BTB was quantified by autoradiography and reported as a unidirectional transport, Ki, for [14C]dextran (Mr 70,000) and [14C]aminoisobutyric acid (Mr 103,000), with or without inhibition of cyclic GMP-specific phosphodiesterase or soluble guanylate cyclase. We also determined cyclic GMP levels in tumors and normal brain, with or without intracarotid bradykinin infusion, using RIA. Intracarotid infusion of bradykinin selectively increased permeability in RG2 tumors and C6 tumors for both tracers. Simultaneous infusion of bradykinin and a cyclic GMP-specific phosphodiesterase inhibitor, zaprinast (20 mg/kg), resulted in significantly increased permeability across the BTB, compared to intracarotid bradykinin infusion alone. Zaprinast also significantly prolonged the permeability effects of bradykinin. Pretreatment using i.v. infusion of the soluble guanylate cyclase inhibitor, LY-83583 (125 microg/kg), significantly attenuated the bradykinin effect of opening the BTB. Cyclic GMP levels in RG2 and C6 tumors were significantly increased after intracarotid bradykinin infusion (2.8- and 2.2-fold, respectively). Cyclic GMP levels in normal brain were not increased by bradykinin infusion. These results show that increasing cyclic GMP in tumor microvessels can increase permeability in response to bradykinin.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1999

Endothelial permeability of the afferent arteriole and its changes as the result of alteration in the activity of the renin-angiotensin system.

Recent studies have demonstrated fenestrations in the juxtaglomerular part of the afferent arteriole facing the extraglomerular mesangium and the epithelioid cells in different mammals including humans. The permeability of the endothelium in afferent arteriole may play an important role in various physiologic and pathophysiologic processes. This study therefore was conducted to examine the permeability along the length of afferent arteriole using ferritin particles as an indicator of permeability/fenestration. Assuming the presence of a relationship between the development of permeable endothelial fenestration and renin formation, the permeability of the endothelium and renin granulation and their correlation along the wall of the afferent arteriole under control conditions and during inhibition of renin-angiotensin system by converting enzyme inhibition or AT1 receptor blockade were examined. The intra-aortically administered ferritin particles appeared in the interstitium of the distal part of the afferent arterioles. About one-third to half of the length of the afferent arteriole wall was ferritin-positive. There was a correlation between ferritin-positive and renin-positive portions. The density of ferritin particles was high close to the glomerulus and decreased continuously, similar to the profile of renin distribution. There was also a correlation between ferritin density in basal membrane and the renin granulation index. On the basis of these results, the afferent arteriole, according to its endothelial permeability, can be divided into two distinct portions, i.e., the permeable and the nonpermeable, the length and ratio of which may be related to the actual renin formation. These portions not only are different in the presence or absence of fenestration of the endothelium, but they also show difference in myosin and renin contents, suggesting that each portion may serve different function(s).

Angiotensin Receptor Antagonists↗
PubMed2002

MRI and fluorescence microscopy of the acute vascular response to VEGF165: vasodilation, hyper-permeability and lymphatic uptake, followed by rapid inactivation of the growth factor.

Vascular endothelial growth factor (VEGF) is one of the key growth factors regulating tumor angiogenesis and thus it is one of the primary targets for antiangiogenic therapy. The long-term effects of VEGF include induction of proliferation and migration of endothelial cells, tube formation and maintenance of the immature capillaries. The early effects of VEGF include vasodilation and increased permeability. We hypothesize that the early responses to VEGF can serve to develop a quantitative measure of the activity of VEGF, and therefore may be applicable for monitoring the efficacy of systemic suppression of VEGF signaling during antiangiogenic therapy. For that end we tested the ability of MRI and fluorescence microscopy to detect the early response to intradermal VEGF165 in nude mice. VEGF-induced local vasodilation and increased permeability was detected by intravenous administration of macromolecular biotin-BSA-GdDTPA(23) 30 min after intradermal administration of VEGF. Contrast leak showed saturation kinetics. Delayed contrast administration (90 min after intradermal administration of VEGF) resulted in low contrast leak and demonstrated that the saturation kinetics is not due to contrast equilibration between plasma and the interstitial space, but rather is due to suppression of vascular permeability. Permeability was restored by a second bolus of VEGF, showing that the saturation kinetics is primarily due to inactivation of the growth factor. Confocal microscopy of fluorescent BSA-FITC confirmed the permeability changes monitored by MRI. Moreover, confocal microscopy showed efficient lymphatic uptake of the extravasated contrast material specifically in regions of VEGF induced hyper-permeability.

Animals↗
PubMed2001

Free fatty acid effects on mitochondrial permeability: an overview.

A variety of experimental conditions elicit increases in mitochondrial permeability that can be differentiated from the classic cyclosporin A (CsA)-sensitive mitochondrial permeability transition (MPT). For example, butylated hydroxytoluene, signal peptides, and the hormone thyroxine have been shown to promote increases in mitochondrial permeability that are CsA-insensitive. Our laboratory has recently demonstrated that palmitic acid, a saturated 16-carbon free fatty acid (FFA), can also open a CsA-insensitive pore. This nonclassic permeability transition (NCPT) is further distinguished by a nonselective dependence on divalent cations and by spontaneous closure. To determine if induction of the NCPT is specific to palmitic acid and to resolve conflicting reports as to the mechanisms by which FFAs alter mitochondrial permeability, we examined in detail mitochondrial swelling induced by FFAs that differ in chain length and degree of saturation. The following results were obtained: (1) In the presence of modest Ca2+ concentrations (75 nmol/mg protein), medium-chain FFAs (C12-C18) were more effective in eliciting mitochondrial swelling than were shorter or longer FFAs; medium-chain alkanols and amines had no effect. (2) Under these conditions, saturated FFAs induced CsA-insensitive swelling with all the characteristics of the NCPT, while unsaturated FFAs triggered the MPT. (3) When matrix Ca2+ concentration was further elevated, unsaturated FFAs triggered the NCPT. (4) Mitochondrial swelling induced by saturated FFAs was inhibited by unsaturated FFAs but not by other saturated FFAs or medium-chain alkanols. These results suggest that ambient conditions can greatly influence the nature of the increase in mitochondrial permeability induced by FFAs. They are also consistent with our earlier proposal that Ca2+ (or Sr2+) binding to FFAs in the inner leaflet of the inner mitochondrial membrane underlies the NCPT.

Animals↗