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1 Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona 85724-5051; and 2 Department of Anatomy, University of California, San Francisco, California 94143-0452
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Inhibition of nitric oxide (NO) synthesis
using NG-nitro-L-arginine methyl
ester (L-NAME) or
NG-monomethyl-L-arginine
(L-NMMA) increases venular
permeability in the rat mesentery (I. Kurose, R. Wolf, M. B. Grisham,
T. Y. Aw, R. D. Specian, and D. N. Granger. Circ.
Res. 76: 30-39, 1995), but the cellular mechanisms
of this response are not known. This study was performed to determine
whether such venular leaks are associated with changes in the
endothelial actin cytoskeleton. In anesthetized Sprague-Dawley rats,
the microvasculature of a mesenteric window was perfused with buffered
saline, with or without 10
5
M L-NAME,
L-NMMA, or the inactive
enantiomer
NG-nitro-D-arginine
methyl ester for 3 or 30 min. FITC-albumin was added to the perfusate
for the last 3 min. The vasculature was perfusion fixed, stained for
filamentous actin and for mast cells, and viewed microscopically. In
control preparations, venules showed few FITC-albumin leaks and the
endothelial actin cytoskeleton consisted of a peripheral rim along the
cell-cell junctions. Preparations treated with
L-NAME or
L-NMMA showed significantly more
leakage, the actin rims in leaky venules were discontinuous, and short, randomly oriented fibers appeared within the cells. In nonleaky venules, the peripheral actin rims sometimes contained small, equally
spaced discontinuities not seen in control preparations. Although a
mast cell stabilizer was used, 27-70% of the mast cells were
degranulated in the presence of
L-NMMA. Thus inhibition of NO
synthesis alters the endothelial cytoskeleton and increases albumin
leakage from mesenteric venules, either directly or indirectly via the
involvement of mast cells.
rat mesentery; confocal microscopy; endothelium; mast cells
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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PREVIOUS STUDIES demonstrated that exposure of microvascular preparations to competitive inhibitors of nitric oxide synthase (NOS) such as NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) decreases levels of cGMP in endothelial cells and increases venular permeability. The enantiomer NG-nitro-D-arginine methyl ester (D-NAME), which is identical to L-NAME except that it does not compete for NOS and thus does not inhibit production of nitric oxide (NO), has no effect on vascular permeability. Kurose et al. (9, 10) and Kubes and Granger (7) showed in the rat mesentery and feline small intestine, respectively, that these inhibitors cause a rapid (within 10 min) increase in venular permeability that is independent of leukocyte adhesion. This is followed by a leukocyte-dependent increase in permeability that is detected after 30 min. In the rat, both phases of increased permeability are inhibited by the permeable analog of cGMP, 8-bromoguanosine 3',5'-cyclic monophosphate. It was hypothesized that depletion of cGMP by NO inhibitors would block cGMP-dependent dephosphorylation of myosin light chain (19, 20), leading to endothelial contraction and possible opening of interendothelial junctions (15, 25). It is likely that endothelial cell retraction, if it occurs, would be accompanied by alterations in the endothelial actin cytoskeleton. However, no studies have been reported that directly demonstrate the cytoskeletal effects of NO inhibition in blood vessels.
Inhibition of NO synthesis may also exert its effects on venular permeability by causing mast cell degranulation and consequential release of mediators, such as histamine, that then act on the endothelial cells, possibly in combination with leukocytes. Kubes et al. (8) have shown in the rat mesentery that inhibition of NO synthesis causes mast cell degranulation. In cultured cells this occurs both as a direct effect of the NOS inhibitor (L-NAME) on mast cells (i.e., independent of endothelium) and via endothelium-derived superoxide that would normally be scavenged by NO (17). Thus any of the wide range of mediators that are released from mast cells could be responsible for the observed increase in microvascular permeability, either by themselves or in conjunction with leukocytes. As yet, no studies have been reported in which the direct effects of NO inhibition on endothelial integrity in vivo have been separated from effects mediated by mast cells. Although mast cell stabilizers have been used to limit degranulation, these are not 100% effective in the presence of NOS inhibitors.
Understanding the mechanisms that promote the effects of NO on microvascular permeability is further complicated by the fact that in some preparations inhibition of NOS decreases, rather than increases, permeability. Such preparations include the hamster cheek pouch (11-13) and the isolated porcine coronary venule (26). Consistent with these studies was the observation that sodium nitroprusside, which releases NO, causes increased permeability of single perfused frog mesenteric capillaries (14). In the latter two preparations leukocytes were absent. Mast cells may have been present in all three, but it is possible that they were not as sensitive to degranulation as those found in the rat mesentery. It is interesting that Mayhan (11) suggested that increased NO might increase permeability by causing endothelial contraction, whereas Kubes (6) hypothesized that inhibition of NO might cause exactly the same response.
We have previously shown that discrete venular leaks, which are produced in the mesentery by histamine (3, 23, 24), are accompanied by breaks in the actin fibers located subjacent to the endothelial cell membrane at cell-cell junctions (1, 21, 22). We have referred to these structures as the endothelial peripheral actin rims (PAR). This observation is consistent with Drenckhahn's hypothesis (2) that there may be no active contraction of the endothelial cell per se in response to inflammation but that, instead, interendothelial gaps are formed because cell-cell adhesion is disrupted due to a change in the actin filaments along the junction. The present study was performed to determine the effect of inhibition of NO synthesis on venular endothelial leakage, specifically with regard to characterizing leak size, location of leaks, and changes in the actin cytoskeleton. The effects of inhibition of NO synthesis on these parameters are compared with those of histamine, relating to our previous studies.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Cannulation and perfusion of rat mesentery. The procedure was similar to that described previously (1) and is summarized here. Thirty male Sprague-Dawley rats (350-400 g) were anesthetized with an intramuscular injection of pentobarbital sodium (6 mg/100 g). After tracheotomy, 0.9 ml of the mast cell stabilizer cromolyn (2.5 mg/ml; Sigma, St. Louis, MO) was injected via the jugular vein. This dose was similar to that used by other investigators in the same preparation (5). The same dose was repeated 30 min later. The abdomen was opened, and several contiguous well-vascularized mesenteric windows were selected and spread out flat over a Plexiglas platform. The superior mesenteric artery was cannulated near the selected mesenteric windows, and the appropriate arterioles and venules bordering the windows were ligated to allow perfusion only of the chosen windows.
The mesenteric windows were flushed clear of blood with HEPES-buffered saline (HBS, pH 7.4) containing 0.5% BSA and 1 U/ml heparin at 37°C and perfused, at an inlet pressure of 100 mmHg, with either HBS-BSA alone (controls, 4 animals for 3 min, 2 animals for 30 min) or HBS-BSA plus one of the following: 105 M
L-NAME (6 animals for 30 min),
105 M
L-NMMA (8 animals for 3 min, 6 animals for 30 min), and
105 M
D-NAME (4 animals for 30 min).
During the last 3 min of each perfusion, 0.05% FITC-albumin (Sigma)
was added to the perfusate. As soon as the vasculature of the windows
was filled with FITC-albumin, as judged by the color, the pressure was
adjusted to 40 mmHg and the portal vein, which acted as the flow
outlet, was clamped. After 3 min, the clamp was removed and 3 ml of
fixative (3% formaldehyde in HBS) were perfused via the cannula at a
pressure of 100 mmHg. Next, the pressure was reduced to 40 mmHg, the
portal vein was clamped, and fixation was continued for 30 min. The
vasculature of the mesenteric windows was then perfused, via the
cannula, with a cocktail of 3% formaldehyde, 0.1% Triton X-100, and
rhodamine phalloidin (10 U/ml) (Molecular Probes, Eugene, OR) in HBS
for 30 min at 4°C to promote staining of endothelial actin fibers. After staining, the vasculature was perfusion fixed for 30 min with 3%
formaldehyde and then flushed with HBS. The mesenteric tissue was
carefully excised and mounted between two thin glass coverslips using
aqueous mounting medium (Vectashield, Vector Laboratories, Burlingame,
CA). In three L-NMMA 3-min
experiments and three controls (HBS-BSA alone), the fixed mesenteric
windows (several from each experiment) were excised, spread flat on
microscope slides, and suffused with 1% toluidine blue for 15 min,
before being flushed with HBS and mounted. Toluidine blue was used to stain the mast cells to determine the percentage that had degranulated. This process was repeated on three preparations that had been subjected
to 104 M histamine for 3 min, for comparison. To gain a representative sample of the degree of
mast cell degranulation in each preparation, 10 fields of view (each a
1-mm-diameter circle) were randomly chosen from the mesenteric windows
and the mast cells were scored as degranulated or not. The total number
of mast cells scored for each preparation was ~100.
Assessment of venular leakage.
An assessment of overall vascular leakage was made by measuring the
number and area of regions with extravascular FITC-albumin. Slides were
examined using a Zeiss Axioplan microscope with ×10 objective,
numerical aperture (NA) 0.6, fitted for epifluorescence. The light source was a 100-W Hg lamp for epifluorescence and a halogen
lamp for transmitted illumination. A video camera (Optronix VI 470) was
mounted at the camera port of the microscope. Five images of leaky
vessel networks from each mesentery, produced by epifluorescence with
the appropriate FITC excitation and emission filters (
= 488 and 515 nm, respectively), were viewed on a black-and-white monitor and also
recorded on a video recorder. Recordings were also made of the networks
under transillumination. Videotaped images were later analyzed using an
analog-to-digital converter and appropriate software (NIH Image) to
measure the length and diameter of each venule, the number of leaks per
venule, and the area of each leak. If a leak was positioned at a
vascular junction, the leak area was divided by the number of venules
involved. Data were pooled within each group (i.e.,
L-NMMA for 3 min), and the following values were calculated: 1)
average number of leaks per length of venule,
2) average leak area per micrometer
of venule, and 3) size distribution
of leaks. Leaks were divided into two categories according to size:
contained leaks were defined as leaks that did not extend beyond the
area of one endothelial cell, and extended leaks were defined as leaks
that involved the boundaries of three or more adjacent endothelial
cells.
Actin cytoskeleton. Epifluorescence microscopy was used to examine the structure and degree of integrity of the endothelial actin cytoskeleton of mesenteric venules from all groups. Photographs of venules were taken, in pairs, using the FITC filter and rhodamine filter in turn, through a 63×, NA 1.25 oil-immersion objective. The photographs were taken to record representative examples of leaky and nonleaky venules, and the only criterion used for selecting a vessel for photography was its clarity under epifluorescence microscopy. The total number of venules that were photographed for HBS-BSA, D-NAME (30 min), L-NMMA (3 min), L-NMMA (30 min), L-NAME (3 min), and L-NAME (30 min) preparations were 51, 35, 33, 21, 28 and 93, respectively. The specimens were also viewed with a confocal microscope (Zeiss LSM 410) equipped with a krypton-argon laser. With the use of a 40×, NA 1.0 oil-immersion objective lens, a venule of interest was identified and a series of images were collected at different focus levels (step size 1 µm) using the 568-nm line for rhodamine phalloidin and the 488-nm line for FITC-albumin.
Statistical analysis. Values from the different groups were compared at different time points using Student's t-test with a P value <0.05 to indicate statistical significance. All values are presented as means ± SE. In these studies, n is the number of venules per group. To compare size distributions of leaks between groups, the Kolmogorov-Smirnov two-sample test was used.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Distribution of leaks. Microscopic examination of control mesenteric preparations by epifluorescence revealed very few leaky sites after perfusion with HBS-BSA for 3 (4 experiments) or 30 (2 experiments) min or with D-NAME for 30 min (4 experiments). Preparations treated with L-NMMA for 3 or 30 min (8 and 6 experiments, respectively) or with L-NAME for 30 min (6 experiments) showed many leaky sites. The leakage occurred in venules but not arterioles or capillaries. The percentage of venules that showed leaks and the total number of venules examined for HBS-BSA, D-NAME (30 min), L-NMMA (3 min), L-NMMA (30 min), and L-NAME (30 min) preparations were 18 (n = 244), 6 (n = 112), 71 (n = 179), 41 (n = 66), and 51% (n = 396). Treatment with L-NMMA, L-NAME, or histamine caused leakage in venules of all sizes. For example, after 3-min treatment with L-NMMA, leakage occurred in 71% of venules 15-30 µm in diameter, 71% of venules from 30 to 55 µm, and 75% of venules >55 µm.
The distributions of leak sizes for preparations treated with L-NMMA or L-NAME are shown in Fig. 1. After 3-min L-NMMA treatment, most leaks were <500 µm2 in area (Fig. 1A). After 30-min treatment with L-NMMA, the size distribution of leaks broadened significantly, that is, the number of small leaks was reduced and the number of large leaks was significantly increased (Fig. 1B). After 30-min treatment with L-NAME, the size distribution of leaks was similar to that produced by 30-min treatment with L-NMMA (Fig. 1C).
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Quantification of leaks. The number of leaks per venule length as a function of type and duration of treatment is shown in Fig. 2A. Previous results for histamine treatment are included in Fig. 2 for comparison. In both saline (HBS-BSA)- and D-NAME-treated vessels, the number of leaks was significantly less than in those subjected to the other treatments. In the case of L-NMMA, but not histamine, the number of leaks was strongly dependent on duration of the treatment, being significantly greater after 3 min than after 30 min. After 3 min L-NMMA produced significantly more leaks than histamine, but after 30 min histamine produced significantly more leaks than L-NMMA. Treatment with L-NAME for 30 min caused a number of leaks similar to that caused by L-NMMA for the same duration.
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Changes in endothelial actin cytoskeleton. In control preparations (those perfused with saline or D-NAME), most venules did not leak FITC-albumin (Fig. 3A). The endothelial cell actin cytoskeleton in venules (Fig. 3B) consisted of peripheral fibers at the cell-cell junctions, which we have called PAR (see arrow) (1, 21, 22), and occasional short fibers in the central portion of the cell (arrowhead). The PAR were regular and almost continuous along cell junctions, although occasional breaks in the PAR were observed.
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Mast cell degranulation.
In the three 3-min control preparations that were stained with
toluidine blue, the percentages of degranulated mast cells were 9, 5, and 9%, respectively. Corresponding values for the L-NMMA preparations
were 35, 27, and 70%, respectively. These compared with values
of 78, 79, and 77%, respectively, that were obtained when mesenteries
were subjected to 104 M
histamine after intravenous injection of cromolyn.
Adherent leukocytes. Although the perfusates used within the isolated mesenteric window vasculature did not contain leukocytes, some leukocytes were seen adhering to venular endothelium after fixation. These leukocytes probably gained entry to the vessels by backflow of venous blood when perfusates were changed, for example, when the treatment solution was replaced by treatment solution plus FITC-BSA. Thus it was unlikely that the leukocytes were in contact with L-NAME or L-NMMA for >3 min. Kubes and Granger (7) showed that it takes ~30 min before L-NAME induces leukocyte adhesion. Therefore, the leukocyte adherence that we observed in some venules was probably not related to the absence of NO.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In this study, the effects of NO synthesis inhibitors on venular permeability and endothelial actin cytoskeleton were determined in situ at two time points. The present study demonstrated that L-NMMA and L-NAME induced venular leaks of a range of sizes within a single preparation, and that the size distribution did not change very much when treatment was extended from 3 to 30 min. This study has also demonstrated several morphological events that accompany the venular leakage induced by inhibition of NO. These include changes in the endothelial actin cytoskeleton and degranulation of mast cells, even in the presence of mast cell stabilizers. Each effect of inhibition of NO synthesis is discussed in turn below and compared with previous results obtained after histamine application.
Venular leakage. The luminal surface area of endothelial cells ranges from 400 to 900 µm2 (1). This means that most leaks produced by treatment with L-NMMA for 3 min covered a region of less than one cell area and thus were considered to be contained leaks. However, a small number of large leaks were also visible. This leak distribution was very similar to that previously observed after 3-min histamine treatment (1). The previous study showed that after 10-min histamine treatment the leak size distribution widened considerably, but after 30 min the distribution became more narrow. Thus the histamine response was transient. In the case of L-NMMA, there was a slight, but significant, widening of the leak size distribution after 30-min treatment compared with 3 min. Increasing treatment time from 3 to 30 min reduced the number of leaks but had little effect on leak area, whereas, for histamine, comparison between 3- and 30-min treatment times demonstrated an increase in leak area but little effect on the number of leaks. These results suggest that during treatment with L-NMMA, the leaks either coalesce to form fewer, larger leaks, or that some of the small leaks seal and the larger leaks increase slightly in size.
Changes in endothelial actin cytoskeleton. With regard to the cytoskeletal alterations after treatment with inhibitors of NO synthesis, one point to note is that some of these changes were also seen after histamine treatment, but others were not. In addition, the whole range of cytoskeletal changes that were observed after 30 min were also evident after 3 min. This is in contrast to the time dependence of the cytoskeletal alterations observed after histamine (1). One similarity with respect to treatment with histamine was the association of contained leaks with focal discontinuities in the PAR. In tandem with this was our observation of focal discontinuities in PAR without accompanying leaky spots, indicating that the disruption of the PAR, alone, is not sufficient to cause leakage. An additional process, perhaps involving redistribution of other junctional proteins such as cadherins, the intramembranous anchoring proteins that connect to F actin via catenins, may also be necessary. The extensive disruption of the actin cytoskeleton and occasional areas of diffuse F actin accompanying extended leaks were also seen with histamine.
One difference between the effects of NO synthesis inhibition and histamine application on the endothelial actin cytoskeleton was the timing of the appearance of actin fibers in the central region of the cell. They were seen in nonleaky venules, and in endothelial cells adjacent to leaks, only 3 min after inhibition of NO synthesis. Central fibers were not seen this early after histamine treatment; it usually took 10-15 min before they could be observed. In addition, the central fibers seen after histamine treatment were usually short and randomly oriented, whereas, after treatment with L-NAME or L-NMMA, the fibers were longer and oriented to a greater extent with the longitudinal axis of the vessel. We speculated that the formation of central fibers after histamine treatment was connected with leak recovery rather than with leak formation, first, because they did not appear until the leaks were regressing and, second, because they were rarely found in endothelial cells that were directly involved in a leak. The latter statement still holds true after inhibition of NO, and so it is possible that the central fibers also fulfill a defensive mechanism in this case. One novel observation concerning the effect of NO inhibition on the actin cytoskeleton was the appearance of uniformly spaced, small discontinuities in the PAR of endothelial cells in nonleaky venules. The fact that they appeared in response to two different NO-inhibitors, L-NMMA and L-NAME, and that they were not seen after treatment with the enantiomer of L-NAME, D-NAME, suggests that they were indeed triggered by inhibition of NO. Once more, the fact that these regular discontinuities were never seen in cells involved in leaks indicates that some other factor is involved in leak formation besides local interruption of the PAR.Mast cell degranulation. The mesentery contains a high density of connective tissue mast cells, which can degranulate and release histamine and other inflammatory mediators. Previous experiments indicate that mast cells can be degranulated by superoxide (8). Concentrations of superoxide anion are regulated by NO, which acts as a scavenger for this substance. Thus depletion of NO could lead to mast cell degranulation, and addition of NO donors could reduce degranulation. Both these responses have been demonstrated in the rat mesentery (4, 8). Although cromolyn was used as a mast cell stabilizer in these experiments, 5-10% of the mast cells degranulated in control preparations and 27-70% degranulated in the presence of L-NAME. Niu et al. (17) have shown previously that addition of mast cells in a ratio as low as 1 mast cell to 50 neutrophils is sufficient to cause a large increase in neutrophil adherence to endothelium. Because of their potency and strategic location, we cannot rule out mast cell secretory products as contributors to at least part of the leak production and endothelial cell cytoskeletal rearrangement. Differences in the type, sensitivity, and density of mast cells between species, and between tissue types, could account for the wide spectrum of alterations in microvascular permeability induced by inhibition of NO. For example, NO increases venular permeability in the hamster cheek pouch (11, 13), isolated porcine venule (26), and frog isolated mesenteric venule (14) but decreases permeability in the rat mesenteric circulation (9).
Irrespective of the presence of mast cells, several lines of evidence suggest that inhibition of NO has a direct effect on the venular endothelium. First, inhibition of NO results in a reduction of intracellular cGMP (16), which in cultured endothelial cells leads to contraction of actomyosin filaments and possible cell contraction to produce a widening of the intercellular clefts (18). Second, levels of superoxide anions, produced by mitochondrial function, may increase if there is less NO available to scavenge the superoxide (8). Excess quantities of superoxide anions may lead to tissue damage. However, because all of the venules in a given preparation will be subjected to these effects and not all of them leak, it is possible that the direct effects of NO inhibition may just lead to a low-grade disruption of the endothelial PAR (the regularly spaced disruptions). Leaks may form either when the direct effects become particularly intense or when the indirect effects, mediated, for example, by mast cells, are superimposed. It is likely that venules in different areas of a given preparation will be subjected to differing degrees of indirect effects, and this would explain the variability between venules in the same preparation in their responses to NO inhibitors. In summary, we have shown that inhibition of NO causes leaks to develop in rat mesenteric venules, similar to those produced by histamine. The leaks are accompanied by changes in the endothelial actin cytoskeleton, consistent with formation of interendothelial gaps and others that may counteract leak formation. Unlike histamine treatment, however, the same types of cytoskeletal rearrangements are present after 3-min NO inhibition as after 30-min inhibition. Local discontinuities of the PAR are necessary, but not sufficient, for leak formation. Mast cells also may play a role in leak formation. Thus inhibition of NO may affect venular permeability directly or indirectly via effects on leukocytes and mast cells. This complexity of initiating factors may explain the variety of cytoskeletal changes that are rapidly manifested after treatment with inhibitors of NO and also may account for the wide spectrum of effects on venular permeability in different preparations and in different animal species.| |
ACKNOWLEDGEMENTS |
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We thank Lisa Wilson for expertise in animal surgery and Dirk Hamlin for assistance in collection and analysis of data.
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FOOTNOTES |
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This work was supported in part by the Arizona Disease Control Research Commission and the Research Evaluation and Allocation Committee, University of California.
Address for reprint requests: A. L. Baldwin, Dept. of Physiology, College of Medicine, Univ. of Arizona, Tucson, AZ 85724-5051.
Received 13 August 1997; accepted in final form 3 February 1998.
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REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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1.
Baldwin, A. L.,
and
G. Thurston.
Changes in endothelial actin cytoskeleton in venules with time after histamine treatment.
Am. J. Physiol.
269 (Heart Circ. Physiol. 38):
H1528-H1537,
1995
2.
Drenckhahn, D.
Cell motility and cytoplasmic filaments in vascular endothelium.
In: Prog. Appl. Microcirc. Basel: Karger, 1983, vol. 1, p. 53-70.
3.
Fox, J.,
F. Galey,
and
H. Wayland.
Action of histamine on the mesenteric microvasculature.
Microvasc. Res.
19:
108-126,
1980[Medline].
4.
Gaboury, J. P.,
X.-F. Niu,
and
P. Kubes.
Nitric oxide inhibits numerous features of mast cell-induced inflammation.
Circulation
93:
318-326,
1996
5.
Johnston, B.,
S. Kanwar,
and
P. Kubes.
Hydrogen peroxide induces leukocyte rolling: modulation by endogenous antioxidant mechanisms including NO.
Am. J. Physiol.
271 (Heart Circ. Physiol. 40):
H614-H621,
1996
6.
Kubes, P.
Nitric oxide-induced microvascular permeability alterations: a regulatory role for cGMP.
Am. J. Physiol.
265 (Heart Circ. Physiol. 34):
H1909-H1915,
1993
7.
Kubes, P.,
and
D. N. Granger.
Nitric oxide modulates microvascular permeability.
Am. J. Physiol.
262 (Heart Circ. Physiol. 31):
H611-H615,
1992
8.
Kubes, P.,
S. Kanwar,
X.-F. Niu,
and
J. P. Gaboury.
Nitric oxide synthesis inhibition induces leukocyte adhesion via superoxide and mast cells.
FASEB J.
7:
1293-1299,
1993[Abstract].
9.
Kurose, I.,
P. Kubes,
R. Wolf,
D. C. Anderson,
J. Paulson,
M. Miyasaka,
and
D. N. Granger.
Inhibition of nitric oxide production. Mechanisms of vascular leakage.
Circ. Res.
73:
164-171,
1993[Abstract].
10.
Kurose, I.,
R. Wolf,
M. B. Grisham,
T. Y. Aw,
R. D. Specian,
and
D. N. Granger.
Microvascular responses to inhibition of nitric oxide production: role of active oxidants.
Circ. Res.
76:
30-39,
1995
11.
Mayhan, W. G.
Role of nitric oxide in modulating permeability of hamster cheek pouch in response to adenosine 5'-diphosphate and bradykinin.
Inflammation
16:
295-305,
1992[Medline].
12.
Mayhan, W. G.
Role of nitric oxide in leukotriene C4-induced increases in microvascular transport.
Am. J. Physiol.
265 (Heart Circ. Physiol. 34):
H409-H414,
1993
13.
Mayhan, W. G.
Nitric oxide accounts for histamine-induced increases in macromolecular extravasation.
Am. J. Physiol.
266 (Heart Circ. Physiol. 35):
H2369-H2373,
1994
14.
Meyer, D. J.,
and
V. H. Huxley.
Capillary hydraulic conductivity is elevated by cGMP-dependent vasodilators.
Circ. Res.
70:
382-391,
1992
15.
Miller, F. N.,
and
D. E. Sims.
Contractile elements in the regulation of macromolecular permeability.
Federation Proc.
45:
84-88,
1986[Medline].
16.
Moncada, S.
The L-arginine oxide pathway.
Acta Physiol. Scand.
145:
201-227,
1992[Medline].
17.
Niu, X.-F.,
G. Ibbotson,
and
P. Kubes.
A balance between nitric oxide and oxidants regulates mast cell-dependent neutrophil-endothelial interactions.
Circ. Res.
79:
992-999,
1996
18.
Oliver, J. A.
Endothelium-derived relaxing factor contributes to the regulation of endothelial permeability.
J. Cell. Physiol.
151:
506-511,
1992[Medline].
19.
Rapoport, R. M.,
M. B. Draznin,
and
F. Murad.
Sodium nitroprusside-induced protein phosphorylation in intact rat aorta is mimicked by 8-bromo cyclic GMP.
Proc. Natl. Acad. Sci. USA
79:
6470-6474,
1982
20.
Rapoport, R. M.,
M. B. Draznin,
and
F. Murad.
Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation.
Nature
306:
174-176,
1983[Medline].
21.
Thurston, G.,
and
A. L. Baldwin.
Endothelial actin cytoskeleton in rat mesenteric microvasculature.
Am. J. Physiol.
266 (Heart Circ. Physiol. 35):
H1896-H1909,
1994
22.
Thurston, G.,
A. L. Baldwin,
and
L. M. Wilson.
Changes in endothelial actin cytoskeleton at leakage sites in the rat mesenteric microvasculature.
Am. J. Physiol.
268 (Heart Circ. Physiol. 37):
H316-H329,
1995
23.
Wu, N.,
and
A. L. Baldwin.
Transient venular permeability increase and endothelial gap formation induced by histamine.
Am. J. Physiol.
262 (Heart Circ. Physiol. 31):
H1238-H1247,
1992
24.
Wu, N.,
and
A. L. Baldwin.
Possible mechanism(s) for permeability recovery of venules during histamine application.
Microvasc. Res.
44:
334-352,
1992[Medline].
25.
Wysolmerski, R. B.,
and
D. Lagunoff.
Involvement of myosin light-chain kinase in endothelial cell retraction.
Proc. Natl. Acad. Sci. USA
87:
16-20,
1990
26.
Yuan, Y.,
H. J. Granger,
D. C. Zawieja,
and
W. M. Chilian.
Flow modulates coronary venular permeability by a nitric oxide-related mechanism.
Am. J. Physiol.
263 (Heart Circ. Physiol. 32):
H641-H646,
1992
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  J. C. Arciero, B. E. Carlson, and T. W. Secomb Theoretical model of metabolic blood flow regulation: roles of ATP release by red blood cells and conducted responses Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1562 - H1571. [Abstract] [Full Text] [PDF]
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S. Y. Yuan New insights into eNOS signaling in microvascular permeability Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1029 - H1031. [Full Text] [PDF]
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 D. Predescu, S. Predescu, J. Shimizu, K. Miyawaki-Shimizu, and A. B. Malik Constitutive eNOS-derived nitric oxide is a determinant of endothelial junctional integrity Am J Physiol Lung Cell Mol Physiol, September 1, 2005; 289(3): L371 - L381. [Abstract] [Full Text] [PDF]
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M. I. Ginsburg and A. L. Baldwin Disodium cromoglycate stabilizes mast cell degranulation while reducing the number of hemoglobin-induced microvascular leaks in rat mesentery Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1750 - H1756. [Abstract] [Full Text] [PDF]
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K. S. Mark, A. R. Burroughs, R. C. Brown, J. D. Huber, and T. P. Davis Nitric oxide mediates hypoxia-induced changes in paracellular permeability of cerebral microvasculature Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H174 - H180. [Abstract] [Full Text] [PDF]
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G. W. Payne, J. A. Madri, W. C. Sessa, and S. S. Segal Abolition of arteriolar dilation but not constriction to histamine in cremaster muscle of eNOS-/- mice Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H493 - H498. [Abstract] [Full Text] [PDF]
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 A. J. Casillan, N. C. Gonzalez, J. S. Johnson, D. R. S. Steiner, and J. G. Wood Mesenteric microvascular inflammatory responses to systemic hypoxia are mediated by PAF and LTB4 J Appl Physiol, June 1, 2003; 94(6): 2313 - 2322. [Abstract] [Full Text] [PDF]
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A. L. Baldwin, E. B. Wiley, A. G. Summers, and A. I. Alayash Sodium selenite reduces hemoglobin-induced venular leakage in the rat mesentery Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H81 - H91. [Abstract] [Full Text] [PDF]
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T. C. Resta, B. R. Walker, M. R. Eichinger, and M. P. Doyle Rate of NO scavenging alters effects of recombinant hemoglobin solutions on pulmonary vasoreactivity J Appl Physiol, October 1, 2002; 93(4): 1327 - 1336. [Abstract] [Full Text] [PDF]
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A. L. Baldwin, E. B. Wiley, and A. I. Alayash Comparison of effects of two hemoglobin-based O2 carriers on intestinal integrity and microvascular leakage Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1292 - H1301. [Abstract] [Full Text] [PDF]
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D. M. Lenda and M. A. Boegehold Effect of a high-salt diet on oxidant enzyme activity in skeletal muscle microcirculation Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H395 - H402. [Abstract] [Full Text] [PDF]
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 D. S. A. Majid, K. E. Said, S. A. Omoro, and L. G. Navar Nitric Oxide Dependency of Arterial Pressure-Induced Changes in Renal Interstitial Hydrostatic Pressure in Dogs Circ. Res., February 16, 2001; 88(3): 347 - 351. [Abstract] [Full Text] [PDF]
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M. P. Gupta, M. D. Ober, C. Patterson, M. Al-Hassani, V. Natarajan, and C. M. Hart Nitric oxide attenuates H2O2-induced endothelial barrier dysfunction: mechanisms of protection Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L116 - L126. [Abstract] [Full Text] [PDF]
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 M. I. Arcos, C. K. Fujihara, A. Sesso, E. Brandao De Almeida Prado, M. J. Brandao De Almeida Prado, G. De Nucci, and R. Zatz Mechanisms of albuminuria in the chronic nitric oxide inhibition model Am J Physiol Renal Physiol, December 1, 2000; 279(6): F1060 - F1066. [Abstract] [Full Text] [PDF]
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J. G. Wood, J. S. Johnson, L. F. Mattioli, and N. C. Gonzalez Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats J Appl Physiol, October 1, 2000; 89(4): 1561 - 1568. [Abstract] [Full Text] [PDF]
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 Y. Shirasawa, F. Ikomi, and T. Ohhashi Physiological roles of endogenous nitric oxide in lymphatic pump activity of rat mesentery in vivo Am J Physiol Gastrointest Liver Physiol, April 1, 2000; 278(4): G551 - G556. [Abstract] [Full Text] [PDF]
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H. Al-Naemi and A. L. Baldwin Nitric oxide: role in venular permeability recovery after histamine challenge Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H2010 - H2016. [Abstract] [Full Text] [PDF]
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A. L. Baldwin Modified hemoglobins produce venular interendothelial gaps and albumin leakage in the rat mesentery Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H650 - H659. [Abstract] [Full Text] [PDF]
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R. K. Wong, A. L. Baldwin, and R. L. Heimark Cadherin-5 redistribution at sites of TNF-alpha and IFN-gamma -induced permeability in mesenteric venules Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H736 - H748. [Abstract] [Full Text] [PDF]
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