Vascular Permeability Index Research Articles

Aggravating process induced by indomethacin on chronic gastric lesion in rat. Role of polymorphonuclear leucocytes.

The present study examines the indomethacin-provoked aggravation of chronic ulceration induced by acetic acid in rats. The drug was administered in a single dose, 7 and 14 days after provocation of ulceration. The changes induced by indomethacin in other groups of animals that had been treated for 7 and 14 days with hydroxyurea (which provokes a marked leucopenia) were also studied. The results obtained demonstrate that indomethacin does not significantly modify the macroscopic index of ulceration nor vascular permeability in the majority of the groups tested. Only in the group that received hydroxyurea for 14 days was there an increase in both parameters. Myeloperoxidase activity was assayed and used as an index of leucocyte infiltration in an attempt to relate the increase in this activity with a gastrolesive effect. Application of acetic acid produced a significant increase in this activity 7 days after induction of chronic injury. Administration of hydroxyurea intraperitoneally was associated with a decrease in the severity of chronic ulceration and neutrophil infiltration into the gastric mucosa. This effect was detectable enzymatically and microscopically. The groups that received indomethacin showed an increase in myeloperoxidase activity, although this increase was only significant in the animals treated with hydroxyurea for 7 and 14 days. The results suggest that the aggravation provoked by indomethacin is greater when the ulcer curing process is more advanced.

Distribution of Regional Density and Vascular Permeability in the Adult Respiratory Distress Syndrome

Although recent X-ray computed tomography (CT) data show that ventral-dorsal gradients in density are common in the adult respiratory distress syndrome (ARDS), we hypothesized that the ventral-dorsal gradient of pulmonary vascular permeability would be evenly distributed in patients with ARDS. We tested this hypothesis by analyzing previously reported data (Am Rev Respir Dis 1991; 143:150–154) obtained by the nuclear medicine imaging technique of positron emission tomography (PET). Measurements of regional lung density (LD), extravascular density (EVD), and the pulmonary transcapillary escape rate (PTCER; an index of vascular permeability) were obtained in eight patients with ARDS and in 10 normal subjects. The data from four contiguous tomographic slices were organized into 20 anatomically oriented “bins” from the ventral (Bin #1) to dorsal (Bin #20) position. Mean overall LD, ERD, and PTCER were all significantly higher (p < 0.05) in the ARDS patients than in normal subjects. Regression slopes of LD ver...

Effect of alpha and beta-adrenergic agonists on methacholine-induced nasal secretion in man

To examine the roles of alpha-adrenergic, beta-adrenergic and cholinergic agonists on the nasal secretion mechanism, the author repeated nasal methacholine (Mch, 1 time 20 mg) challenges ten times at 10-min intervals in 13 healthy male subjects. As it was difficult to obtain a sufficient amount of nasal secretion for analysis using simple nasal provocation tests with alpha-and beta-adrenergic agonists before repeated Mch challenges, alpha-adrenergic (phenylephrine, Phe, 2 mg) and beta-adrenergic (isoproterenol, Iso, 0.2 mg) agonists were administered into both nostrils. The effects of these agents on the volume of nasal secretions (Vol), the fucose volume (Fu, an index of glandular secretion) and the albumin volume (Alb, an index of vascular permeability) in the Mch induced nasal secretions were analyzed each time. Repeated Mch challenges revealed that the initial challenge produced the largest response as reflected by the Vol, Fu and Alb of the secretions, and by Vol and Fu production being almost constant during the 10 repetitions of Mch challenge at 10-min intervals. However, Alb demonstrated the greatest decrements. Phe administration before Mch challenges gave rise to Fu increasing more markedly while Alb was unchanged. On the other hand, that of Iso before, produced greater decreases in Vol, Fu and Alb levels. Therefore, it is suggested that repeated Mch challenge causes the maintenance of glandular secretion while stopping albumin permeability, that with pre-administration of alpha-agonists glandular secretion increases, and that pre-administration of beta-agonists inhibits glandular secretion. When both alpha- and beta-agonists are given before the challenge, however, there is no increase in vascular permeability.

Platelet-activating factor stimulates protein tyrosine kinase in hamster cheek pouch microcirculation.

We studied the interactions between platelet-activating factor (PAF) and protein tyrosine kinase (PTK) in the modulation of microvascular responses in the hamster cheek pouch using intravital microscopy and computer-assisted image analysis. Changes in arteriolar diameter and in integrated optical intensity (IOI; an index of vascular permeability) were measured. Fluorescein isothiocyanate-labeled dextran 150 (FITC-Dx 150) served as a tracer for macromolecular transport. Genistein and tyrphostin 25, two PTK inhibitors, were applied topically in separate experiments. Pretreatment with 10(-4), 10(-6), and 10(-8) M genistein and with tyrphostin 25 at 10(-5) and 10(-7) M attenuated the maximal increment in mean IOI (+/- SE) induced by PAF at 10(-7) M (19.9 +/- 5.3, 21.5 +/- 4.5, 58.5 +/- 11.4, 28.7 +/- 7.6, and 35.0 +/- 10.9 vs. 70.7 +/- 8.9 units, respectively). Pretreatment with PTK inhibitors resulted in vasodilation but did not inhibit PAF-induced vasoconstriction. Our results suggest that PTK represents a biochemical pathway involved in the PAF modulation of microvascular permeability but not PAF modulation of arteriolar tone.

Segmental vascular pressures in lung embolism.

Average microvascular filtration pressure and vascular permeability measures were obtained in 100-microns glass bead-embolized dog lung lobes randomly assigned to groups in which isolated perfusion was designed to produce weight gain (edema groups) or no weight gain (isogravimetric groups). The solvent drag reflection coefficient (sigma), an index of vascular permeability, was obtained during edema formation, whereas isogravimetric capillary pressure was obtained during isogravimetry. Vascular permeability increased in response to embolism, because sigma was 0.53 +/- 0.03 vs. 0.80 +/- 0.05 (P < 0.005) in embolized and control lobes, respectively. Vascular occlusion methods indicated the greatest resistance increase in response to embolism in the vascular segment represented by Pao--Pdo (arterial occlusion pressure--double occlusion pressure). Because papaverine vasodilation reduced total vascular resistance (RT; P < 0.05) by decreasing Pao (P < 0.01) without altering Pdo, the RT increase in response to embolism was likely due to both vasoconstriction and obstruction. Because Pdo approximated capillary pressure at isogravimetry, Pdo appears to estimate average filtration pressure in both embolized (n = 6) and control lungs (n = 6). Arterial pressure was 56.2 +/- 13.6 vs. 17.6 +/- 1.5 cmH2O (P < 0.01) in embolized (n = 5) and control lobes (n = 6), respectively, whereas Pdo values of 16.1 +/- 1.5 vs. 12.4 +/- 0.8 (P < 0.05) suggested relatively little increase in filtration pressure in response to embolism. If the beads obstructed 100-microns vessels, the vascular segment represented by Pao--Pdo, the major site of vasoconstriction as well as mechanical obstruction, likely includes 100-microns arteries.

Effects of Capsaicin, (±)-CP-96,345 and SR 48968 on the Bradykinin-induced Airways Microvascular Leakage in Guinea-pigs

Summary: The aim of this study was to demonstrate the involvement of neuropeptides in the increase in microvascular permeability induced by bradykinin in guinea-pig airways in vivo and to determine the type of receptor involved. Extravasation of intravenously injected Evans blue dye was used as an index of vascular permeability. Increase in plasma exudation induced by bradykinin (0.3 μg/kg, iv) was reduced or abolished by capsaicin (40 mg/kg, sc, 7 days before experiments), a drug which destroys neurokinins in the NANC nerve endings. (±)-CP-96,345 (3 mg/kg, iv), an antagonist of neurokinin NK 1-receptors, abolished the increase of vascular permeability induced by bradykinin and reduced or abolished the effects of substance P (0.3 μg/kg, iv). The higher dose of (±)-CP-96,345 (10 mg/kg, iv) completely blocked the effects of substance P, but it did not modify those of neurokinin A (100 μg/kg, iv). In contrast, SR 48968 (0.1 and 0.3 mg/kg, iv), an antagonist of neurokinin NK 2-receptors, reduced the increase of vascular permeability induced by neurokinin A without influencing the effects of bradykinin and substance P. These results demonstrate that a stimulation of the non-adrenergic non-cholinergic (NANC) nerves and a subsequent release of neuropeptides, especially of substance P, is involved in the effects of bradykinin.

Does unilateral orchidectomy influence blood flow, microcirculation and vascular morphology in the remaining testis?

Adult rats were hemi-orchidectomized and various aspects of testicular blood flow, microcirculation and vascular morphology were studied in the remaining testis after 30 days and compared to that in intact sham-operated animals. Testis weight, total testicular blood flow (measured with microspheres), capillary blood flow pattern (studied with laser Doppler flowmetry) and the volume of interstitial fluid in the testis (index of vascular permeability) were all unaffected by hemi-orchidectomy. Morphometric measurements on perfusion-fixed testicular tissue showed that the volume densities of Leydig cells, blood vessels and small exchange blood vessels were increased by hemi-orchidectomy (by approximately 45, 33 and 42%, respectively). The volume density of Leydig cells in individual testes was correlated to the volume and surface density of capillaries + small postcapillary velules (r = 0.72 and 0.86, respectively). Hemi-orchidectomy is known to result in a doubling in testosterone secretion per Leydig cell. This increased endocrine activity results in moderate increase in the vascular exchange area but other aspects of testicular microcirculation and blood flow are apparently unaffected.

A quantitative correlation of extravascular lung water accumulation with vascular permeability and hydrostatic pressure measurements: a positron emission tomography study

In 11 supine dogs, we related regional lung water concentration (rLWC) measurements made with positron emission tomography (PET) after canine oleic acid (OA)-induced acute lung injury to extravascular lung water measurements by the thermal-green dye indicator dilution technique (EVLW-TGD), and to measurements of vascular permeability (also by PET) and hydrostatic pressure. The rLWC measurements correlated well with EVLW-TGD (R 2 = 97%). Changes in LWC did not correlate with either the pulmonary wedge pressure or PET measurements of protein leak (as an index of vascular permeability), but were related when both variables were considered together (R 2 = 73%). Lung water concentration increased significantly 60 minutes after OA, primarily in dorsal, gravity-dependent lung regions, with a small, but statistically significant, change over the next 75 minutes. These data suggest that PET measurements of LWC or EVLW on one tomography slice can be representative of changes in EVLW in the lung as a whole after diffuse lung injury. Furthermore, the magnitude of edema accumulation after acute lung injury can be accurately predicted by quantitative measurements of hydrostatic pressure and of protein leak using PET.

Hemodynamic and Vascular Permeability Effects of Lipid Emulsion in the Isolated Canine Lung Lobe

The isolated canine right lower lung lobe (RLL) perfused with autogenous blood at constant flow was used to study the effects of a parenteral lipid emulsion, Liposyn 10%, on pulmonary hemodynamics and vascular permeability. Lobes were placed into four groups: (1) control lobes (C; n = 6), which were infused via the lobar artery with normal saline at 1 ml.min-1 for 30 min; (2) lipid emulsion lobes (L; n = 6), which were infused via the lobar artery with Liposyn 10% at 1 ml.min-1 for 15 min; (3) lobes infused with both Liposyn 10% and 0.25 to 6.0 mg of lipoprotein lipase (LL; n = 4); and (4) lobes infused with 0.13 to 6.0 mg of lipoprotein lipase alone (LP; n = 6). Liposyn infusion alone caused no changes in lobar hemodynamics compared to group C. Over time there were no differences between groups C and L on venous PO2, PCO2, or pH. Post-infusion weight gain (over 10 to 14 min) averaged 0.23 +/- 0.08, 0.19 +/- 0.07, 0.66 +/- 0.23, and 3.00 +/- 1.46 g.min-1.100 g-1 RLL for groups C, L, LP, and LL, respectively (p less than 0.05, for group LL compared to Group C). The pulmonary filtration coefficient (Kf) was determined as an index of vascular permeability. Groups C and L had Kf values of 0.07 +/- 0.01 and 0.28 +/- 0.22 ml.min-1.mm Hg-1.100 g-1 (mean +/- SE), respectively, which did not differ significantly (p greater than 0.05). Liposyn 10%, given in a concentration larger than that used clinically, produced no untoward pulmonary vascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of pulmonary edema induced by a diacylglycerol second messenger

We investigated the effect of dioctanoylglycerol (DOG), a second messenger of protein kinase C (PKC) activation, in the absence and presence of neutrophils in isolated perfused guinea pig lung. DOG was given after a base-line isogravimetric steady-state period. Pulmonary capillary pressure (Ppc) and change in lung weight (delta W) were monitored at 15, 30, and 60 min. Capillary filtration coefficient (Kf,c, an index of vascular permeability) was measured during base-line period and at 30 min. DOG increased the Ppc and delta W at 30 and 60 min, and the Kfc at 30 min. Monooctanoylglycerol, a monoacylglycerol that does not activate PKC, had no effect on Ppc, Kf,c, and delta W. Pretreatment with two different PKC inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine or staurosporin, prevented the pulmonary response to DOG. With neutrophils present, DOG caused greater increases in delta W and the (wet-dry)-to-dry wt ratio compared with DOG group. Response to DOG+ neutrophils was due to oxygen radical production because it was prevented by pretreatment with catalase and because DOG increased superoxide release from neutrophils. PKC activation using DOG in the isolated lung results in pulmonary edema mediated by increases in capillary pressure and vascular permeability. Lung weight-gain response to DOG is greater in the presence of neutrophils. Response to DOG+ neutrophils is mediated by oxygen radicals.

SOD prevents damage and attenuates eicosanoid release in a rabbit model of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) was produced in anesthetized rabbits by transmural injection of intestinal loops with an acidified solution of casein and calcium gluconate, mimicking the luminal milieu of afflicted neonates. Intravenous infusion of superoxide dismutase (SOD) 15 min after NEC induction prevented intestinal damage. In ex vivo perfused intestinal loops, we determined the sites of eicosanoid release and their contribution to the vascular effects of N-formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) in damaged and SOD-salvaged intestine. The vascular effluent was the primary site of stimulated eicosanoid release. The vascular responses to fMLP (vasoconstriction) and PAF (vasodilation) were not altered by SOD, although vascular resistance was higher in the SOD group. SOD treatment attenuated 1) transmural fluid shifts in ex vivo perfused intestinal preparations, an index of vascular permeability, 2) fMLP-induced prostaglandin E2, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and leukotriene B4 (LTB4) release, and 3) PAF-induced release of 6-keto-PGF1 alpha and LTB4. Stimulated thromboxane B2 release was not altered by SOD. Thus NEC can be established by a luminal insult that causes local generation of free radicals and exaggerated release of prostaglandins and leukotrienes.

PMA-induced pulmonary edema: mechanisms of the vasoactive response.

We investigated the effect of phorbol myristate acetate (PMA) in isolated guinea pig lungs perfused with phosphate-buffered Ringer solution. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight were recorded at 0, 10, 25, 40, and 70 min. The capillary filtration coefficient (Kf), an index of vascular permeability, was measured at 10 and 70 min. The perfusion of PMA (0.5 x 10(-7) M) increased Ppa, Ppc, and lung weight at 70 min. The ratio of arterial-to-venous vascular resistance (Ra/Rv) decreased and the Kf did not change with PMA. The perfusion of the lung with 4 alpha-phorbol didecanoate (inactive toward the protein kinase C analogue of PMA) did not affect the lung. The inhibition of TxA2 synthase with dazoxiben inhibited the response to PMA. The inhibition of the 5-lipoxygenase with U-60257 and the SRS-A receptor antagonist FPL 55712 also prevented the response to PMA. The addition of superoxide dismutase (SOD), catalase, or SOD plus catalase (the enzymes that remove O.2 H2O2, and OH., respectively) did not prevent the PMA effect or the release of TxA2; however, dimethylthiourea (DMTU), a scavenger of OH., did prevent the response to PMA. The data indicate that PMA causes a neutrophil-independent increase in lung weight due to increases in Ppc mediated by TxA2 and SRS-A. The protective effect of DMTU may be due to the inhibition of TxA2 generation.

Noninvasive measurement of regional interstitial lung volume in sheep.

The noninvasive external radioflux detection method (ERD) measures net transvascular flux of tracer protein into and out of the lung extravascular compartment (EV) and time to zero flux between compartments. With this information we can now estimate regional interstitial volume in the field of the external probe (VIs). Dividing the mass of EV tracer by VIs, we obtain interstitial concentration ([Is]). Directly sampling plasma concentration of the tracer, we can construct plasma-interstitium equilibration curves that are analogous to plasma-lymph equilibration curves without invasive surgery. We completed 46 ERD studies in 21 sheep with chronic lung lymph fistulas. Sheep were studied under baseline conditions (n = 30) and after elevating left atrial pressure by mitral obstruction (n = 7), or intravascular volume infusion (n = 8), and increasing lung vascular permeability (n = 1). In each study we compared the slope of the regression through plasma-lymph concentration of tracer protein over time ([P]-[L], measured directly) with that through values of plasma-interstitial concentration ([P]-[Is], assessed noninvasively), an index of vascular permeability. For this correlation, r = 0.94, and the regression line approximates identity. Mean [Is] appears to approximate [L] in sheep.

Lung morphological and permeability changes induced by intravascular coagulation in dogs.

The objectives of this study were to describe the morphological alterations of the pulmonary microvasculature in anesthetized dogs infused intravenously with alpha-thrombin (111-233 NIH U/kg) and to measure the protein reflection coefficient (sigma d), an index of pulmonary vascular permeability to proteins. Quantitative electron microscopy of lung biopsies from a group of four dogs showed an increase in the volume density of the alveolar interstitium and an increase in intravascular fibrin at 30 min after the thrombin infusion. The pulmonary microvascular endothelium was often swollen, blistered, highly vacuolized, or rarefied when close to or in contact with fibrin but appeared normal when not closely associated with fibrin. Fibrin-endothelial interactions often included projections of endothelium surrounding fibrin, the presence of fibrin within endothelial cells, 10- to 15-nm bridges connecting fibrin and endothelium, and disruption of the endothelial plasmalemma in contact with fibrin. Alveolar epithelial cells were unaffected by the thrombin infusion. Pulmonary lymph was collected from an afferent lymphatic to the left tracheobronchial lymph node in a second group of five dogs anesthetized with pentobarbital sodium intravenously. Thrombin increased pulmonary lymph flow by sevenfold and also increased the extravascular lung water-to-bloodless dry lung weight ratio. Left atrial pressure was elevated after thrombin infusion until a filtration-independent state was approached for the calculation of sigma d. Thrombin decreased sigma d from a normal value of 0.62 +/- 0.02 to 0.53 +/- 0.02. Thus thrombin-induced intravascular coagulation in dogs produced focal disruptions of the microvascular endothelium associated with intravascular fibrin and increased the pulmonary vascular permeability to proteins.

Vascular pressure effects on lung edema formation after glass bead embolism.

The canine lung lobe was embolized with 100-micron glass beads before lobectomy and blood anticoagulation. The lobe was isolated, ventilated, and pump-perfused with blood at an arterial pressure (Pa) of about 50 (high pressure, HP, n = 9) or 25 Torr (low pressure, LP, n = 9). Rus/PVR, the ratio of upstream (Rus) to total lobar vascular resistance (PVR), was determined by venous occlusion and the isogravimetric capillary pressure technique. The capillary filtration coefficient (Kf), an index of vascular permeability, was obtained from rate of lobe weight gain during stepwise capillary pressure (Pc) elevation. The embolized lobes became more edematous than nonembolized controls, (C, n = 11), (P less than 0.05), with Kf values of 0.20 +/- 0.04, 0.25 +/- 0.06, and 0.07 +/- 0.01 ml X min-1 X Torr-1 X 100 X g-1 in LP, HP, and C, respectively (P less than 0.05). The greater Rus/PVR in embolized lobes (P less than 0.05) protected the microvessels and, although Pc was greater in HP than in controls (P less than 0.05), Pc did not differ between HP and LP (P greater than 0.05). Although indexes of permeability did not differ between embolized groups (P greater than 0.05), HP became more edematous than LP (P less than 0.05). The greater edema in HP did not appear due to a greater imbalance of Starling forces across the microvessel wall or to vascular recruitment. At constant Pc and venous pressure, elevating Pa from 25 to 50 Torr in embolized lobes resulted in greater edema to suggest fluid filtration from precapillary vessels.

Simultaneous visualization of vascular permeability change and leukocyte egress in the central nervous system during autoimmune encephalomyelitis.

An unresolved issue in the study of demyelinating disease is whether blood-brain barrier damage is dependent upon the migration of inflammatory cells into the central nervous system (CNS). In a study of experimental autoimmune encephalomyelitis (EAE) in rabbits, a freeze-dried, paraffin-embedded tissue technique was exploited to enable (1) the immobilization of intravenously injected sodium fluorescein tracer, as an index of vascular permeability; and (2) an effective labeling by monoclonal antibodies of both T-lymphocytes and mononuclear phagocytes in "unfixed" neural tissue. Using these newly combined methods, evidence was found that increased vascular permeability in the CNS during EAE occurs concomitantly with, and not prior to, infiltration by mononuclear phagocytes.

CHANGES IN BLOOD FLOW AND VASCULAR PERMEABILITY OF THE TESTIS, EPIDIDYMIS AND ACCESSORY REPRODUCTIVE ORGANS OF THE RAT AFTER THE ADMINISTRATION OF CADMIUM CHLORIDE

SUMMARY The effect of s.c. injections of cadmium chloride (3 μmole/100 g. body wt.) on the blood flow and vascular permeability of the testis, epididymis and accessory reproductive organs of rats has been examined. Sapirstein's indicator fractionation technique was used to measure blood flow with [131I]iodoantipyrine and [86Rb]-rubidium chloride. A rubidium-rejecting compartment was found in the testis similar to, but smaller than, that in the brain and pineal body. Testicular blood flow started to decrease within 3 hr. of giving cadmium (Cd) and by 12 hr. was only 2–9 % of the control values; it then started to recover but after 14 days it was still only 31 % of the control values. Apart from a small reduction of blood flow to the first part of the head of the epididymis 6 hr. after Cd administration, blood flow was not strikingly reduced in any part of the epididymis by Cd treatment. However, blood flow to all parts of the epididymis had increased markedly when examined 7 days after giving Cd; this was most evident in the first part of the head of the epididymis. Blood flow through the accessory reproductive organs was reduced within 6 hr. of Cd injection. Blood flow in the seminal vesicles returned to normal between 1 and 14 days after treatment but blood flow in the prostate gland did not recover. The movement of albumin from intravascular to extravascular compartments was used as an index of vascular permeability. This index increased in the testis in the period 1–6 hr. after Cd administration and the change occasionally occurred before blood flow decreased. A similar increase was seen in the first part of the head of the epididymis 3–6 hr. after Cd, but no change was seen in the rest of the epididymis. The evidence suggests that Cd acts by damaging the endothelium of the capillaries in the testis leading to prolonged stoppage of blood flow which would lead to hypoxia in the spermiogenic epithelium.