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Pulmonary and Critical Care Division, Department of Internal Medicine, and Department of Physiology, University of Missouri-Columbia, Columbia, Missouri 65212
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The role of nitric oxide (NO) in
microvascular permeability remains unclear because both increases and
decreases in permeability by NO synthase (NOS) inhibitors have been
reported. We sought to determine whether blood-borne constituents
modify venular permeability responses to the NOS inhibitor
NG-nitro-L-arginine methyl ester
(L-NAME). We assessed hydraulic conductivity
(Lp) of pipette-perfused rat mesenteric venules
before and after exposure to 10
4 M L-NAME. In
the absence of blood-borne constituents, L-NAME reduced
Lp by nearly 50% (from a median of 2.4 × 107
cm · s1 · cmH2O1,
n = 17, P < 0.001). The reduction in
Lp by L-NAME was inhibited by a
10-fold molar excess of L-arginine but not
D-arginine (n = 6). In a separate group of
venules, blood flow was allowed to resume during exposure to
L-NAME. In vessels perfused by blood during
L-NAME exposure, Lp increased by
78% (from 1.4 × 107
cm · s1 · cmH2O1,
n = 10, P < 0.01).
NG-nitro-D-arginine methyl
ester did not affect Lp in either of the two
groups. These data imply that NO has direct vascular effects on
permeability that are opposed by secondary changes in permeability mediated by blood-borne constituents.
microvascular permeability; arginine; endothelium; rat; nitric oxide synthase
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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MICROVASCULAR PERMEABILITY is a dynamic process that may be increased or decreased from basal values by a variety of conditions (11). Hydraulic conductivity (Lp) is a measure of permeability that reflects the ease of passage of water across the vascular barrier. A variety of stimuli capable of modifying Lp include endogenous and exogenous vasodilators (21, 38), shear stress (37), hypoxia and hyperoxia (35), changes in membrane potential (8, 41), and inflammatory mediators (26, 38).
Nitric oxide (NO) derived from the vascular endothelium is an important regulator of local blood flow and pressure (24). The influence of NO on microvascular permeability is less clear, because conflicting results exist in the literature regarding the effects of NO donors and NO synthase (NOS) inhibitors on permeability (9, 14, 32). Some investigators have proposed that microvascular permeability responses to NO are influenced by blood-borne elements, particularly leukocytes (7, 14). NOS inhibitors have been reported to increase leukocyte adhesion to the vascular endothelium (16), and adherent leukocytes have been associated with increases in microvascular permeability (15, 36). Harris (7) reported that the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) increased filtration rate of rat mesenteric capillaries in normal animals but decreased filtration rate in animals depleted of circulating neutrophils or when leukocyte adhesion was inhibited (7). To determine whether blood-borne constituents modify venular permeability responses to NOS inhibition, we examined the influence of L-NAME on rat mesenteric venular Lp in the presence and absence of blood perfusion.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Solutions
On the day of an experiment, 2 liters of bicarbonate-buffered saline (BBS) were prepared from a 20× stock solution. The BBS contained (in mM) 131.9 NaCl, 4.7 KCl, 2.0 CaCl2, 1.2 MgSO4, 20.0 NaHCO3, and 5.0 glucose and was bubbled with a gas mixture containing 5% CO2-5% O2-90% N2 (5). In experiments in which the test solution contained 103 M arginine, the
concentration of NaCl in the BBS used for control Lp measures was increased to control for the
osmolar effects of arginine. The pH was measured (pH meter 420A, Orion
Research) during equilibration with the gas mixture and was maintained
at 7.4 ± 0.05. Perfusate solutions contained a final protein
concentration of 15 mg/ml, either dialyzed rat serum albumin
(essentially globulin free, Sigma no. A4538) or heat-treated and
dialyzed homologous rat serum (age, sex, and weight matched; Harlan).
Rat erythrocytes (1-3%, vol/vol) suspended in the perfusate
solution were used as flow markers for assessment of
Lp.
Animal Preparation
Male Sprague-Dawley rats (~200-250 g; Hilltop Lab Animals, Scottdale, PA) were anesthetized with an intraperitoneal or subcutaneous injection of thiobutabarbital (Inactin; 130 mg/kg body wt; RBI, Natick, MA). A midline abdominal incision was made, and a loop of small intestine was exteriorized to allow visualization of a small section of mesentery. The rats were placed in lateral decubitus on a custom Plexiglas animal tray, the mesentery was draped over a polished quartz pillar (Heraeus-Amersil, Fairfield, NJ), and the intestine was covered with saline-moistened gauze. The animal was positioned on the stage of an inverted microscope (Nikon Diaphot 200 or Leitz Diavert), and the preparation was visualized with either a ×32 or ×20 objective. The mesentery was superfused continuously with gas-equilibrated BBS at 37°C. A venule with brisk flow and <2 adherent leukocytes/100 µm vessel length was cannulated as described below.Determination of Hydraulic Conductivity
Venular Lp was determined by the modified Landis microocclusion technique (13, 23). The assumptions and limitations of this technique have been described previously (2). Briefly, a beveled micropipette connected to a water manometer was used to cannulate a microvessel and control vascular hydrostatic pressure.To measure volume flux (Jv), we occluded the
venule downstream from the cannulation site for a few seconds with a
second glass micropipette. Free movement of cells from the pipette into
the vessel lumen provided evidence that the cannulation was free of leaks when the vessel was occluded. During occlusion, movement of
marker erythrocytes toward the microoccluder represented fluid filtration (Jv) across the venule. The
image of the perfused vessel was videotaped (NC-70 camera, Pulnix
America, Sunnyvale, CA; and a Panasonic AG-7350 video recorder,
Matsushita Electric Industries, Osaka, Japan), together with the image
of a video timer (VTG-33, FOR-A), for later measurement and analysis.
Measurements were performed with a computer-assisted image analysis
program (NIH Image, version 1.6) on a personal computer (Macintosh,
Apple Computer, Cupertino, CA). The measured parameters were vessel
radius (r, in cm), initial distance between marker
erythrocyte and occluder (Xo, in cm), and
initial marker cell velocity [(
x/t), in
cm/s], beginning 2 s after vessel occlusion. With the use of
these parameters, fluid flux per unit surface area
(Jv/S, in cm/s; Eq. 1) was
determined at several vascular hydrostatic pressures (Pv,
in cmH2O)
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(1) |
P) between the vessel (Pv) and interstitium
(Pi) and the product of the reflection coefficient (
)
and oncotic pressure gradient (
) between the vessel
(v) and interstitium (i). Assuming a
negligible Pi and a constant during occlusion,
Lp (in
cm · s1 · cmH2O1)
was determined as the slope of the least-squares regression of
Jv/S on P, with a pressure axis
intercept of (in cmH2O)
![J<SUB>v</SUB><IT>/S=L</IT><SUB>p</SUB>[(P<SUB>v</SUB><IT>−</IT>P<SUB>i</SUB>)<IT>−&sfgr;</IT>(<IT>&pgr;</IT><SUB>v</SUB><IT>−&pgr;</IT><SUB>i</SUB>)]](/content/vol279/issue4/fulltext/H2017/img002.gif)
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(2) |
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(3) |
Experimental Protocols
The tissue was superfused continuously (5 ml/min), and measurements of Lp were begun 2 min after cannulation. After initial measurements of Lp (Lpcontrol) were obtained during superfusion with BBS alone, the superfusate was changed to one of the test solutions. Test measurements of Lp (Lptest) began ~1 min after exposure to the test solution and were continued for 15-30 min. In some experiments, blood flow was allowed to resume during exposure to the test agent with the use of a method described by He et al. (10) and outlined below. Three protocols were performed.Protocol 1: Direct vascular effects of L-NAME on
Lp.
To determine the direct vascular responses to NOS inhibition
independent of blood-borne constituents, we used the arginine analog
L-NAME. After control Lp
measurements were obtained, one group of vessels (n = 10) was superfused with 104 M L-NAME, and
test measurements were repeated. To exclude nonspecific effects of
L-NAME due to charge, we superfused a second group of
vessels (n = 9) with the biologically inactive
enantiomer
NG-nitro-D-arginine methyl
ester (D-NAME) (104 M) as the test solution.
Protocol 2: Influence of arginine on direct effects of
L-NAME on Lp.
To further evaluate the specificity of the responses to
L-NAME, we exposed another group of vessels
(n = 6) to a test solution containing 104
M L-NAME and a 10-fold molar excess of the charged but
biologically inactive isomer D-arginine (103
M). After Lp was measured during exposure to
L-NAME and D-arginine, the test solution was
changed to 104 M L-NAME and 103
M L-arginine, and measurements were repeated. The effects
of L-arginine (103 M) alone on
Lp were assessed in another group of vessels
(n = 4).
Protocol 3: Influence of blood-borne constituents on
Lp responses to L-NAME.
To assess the contribution of blood-borne constituents to the responses
to NOS inhibition, we exposed vessels to L-NAME in the
presence of blood perfusion. After control measurements of Lp were obtained (n = 10), the pipette was removed from the vessel to allow blood flow to
resume (10). The mesentery was then superfused with
104 M L-NAME. After 15 min, the vessel was
recannulated, and test measures were repeated. To control for temporal
effects of L-NAME on Lp, another
group of vessels (n = 7) was exposed to
104 M L-NAME (without removing the pipette
from the venule), and test measures began 15 min after the onset of
exposure to L-NAME. To exclude nonspecific effects of
L-NAME due to charge, we exposed a final group of vessels
to 104 M D-NAME as the test solution during
resumption of blood flow (n = 6).
Statistical Analysis
Absolute values of Lp are expressed as medians ± median absolute deviation, because this parameter is not distributed normally (this study and Ref. 6). All other data are expressed as means ± SE. Statistical analyses were performed with StatView 5.0 software (SAS Institute) and a Macintosh computer. Control and test Lp values in each group were compared by Wilcoxon signed rank test, and control Lp values among groups were compared with the Mann-Whitney U test. To calculate the average test-to-control ratios (Lptest/Lpcontrol) for each group, the logarithm of each ratio was used to weigh equally increases and decreases in Lp. The average response was derived as the antilogarithm of the mean of the logs (19, 32).| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Control Data
The frequency distribution of control values of Lp of 52 venules (diameter = 32.7 ± 1.0 µm) reported here is shown in Fig. 1; median Lp was 1.9 × 107
cm ·s1 · cmH2O1,
and mean Lp was 2.3 × 107
cm · s1 · cmH2O1.
The frequency distribution differed from that of a normal distribution (Kolmogorov-Smirnov normality test, P < 0.05).
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Influence of L-NAME on Venular Lp: Absence of Blood-Borne Elements
Superfusion with the NOS inhibitor L-NAME (n = 10) led to a reduction in venular Lp (Lpcontrol = 2.4 ± 0.8 × 107
cm · s1 · cmH2O1,
Lptest/Lpcontrol = 0.53 ± 0.07, P < 0.01). The inactive
enantiomer D-NAME (n = 9) was without
influence on Lp
(Lpcontrol = 1.9 ± 0.8 × 107
cm · s1 · cmH2O1,
Lptest/Lpcontrol = 0.94 ± 0.07). The effects of L-NAME of decreasing
Lp were evident within 2 min of superfusion of
the test solution (Fig. 2A)
and remained constant during the duration of the experiments.
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To evaluate further the specificity of the responses to
L-NAME, we examined the influence of arginine on the
responses. After control measures of Lp
were obtained, the superfusate was changed to 104 M
L-NAME and 103 M D-arginine as
the first test solution. After Lp was assessed under those conditions, the superfusate was changed to
104 M L-NAME and 103 M
L-arginine. In the presence of D-arginine,
L-NAME led to a reduction in
Lp
(Lpcontrol = 2.6 ± 0.3 × 107
cm · s1 · cmH2O1,
Lptest/Lpcontrol = 0.64 ± 0.05, P < 0.05). However, superfusion
with L-NAME in the presence of a 10-fold molar excess of
L-arginine increased Lp above
initial control values
(Lptest/Lpcontrol = 1.66 ± 0.32, P < 0.05) (Fig.
3). Superfusion with
L-arginine alone (103 M, n = 4) was without influence on Lp
(Lpcontrol = 2.2 ± 0.3 × 107
cm · s1 · cmH2O1,
Lptest/Lpcontrol = 0.9 ± 0.18).
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Influence of Blood-Borne Constituents on Lp Responses To L-NAME
To determine whether exposure to blood-borne elements influence venular permeability responses in the presence of L-NAME, we allowed blood flow to resume in one group of venules after control measures of Lp were obtained. L-NAME (104 M; n = 10) or D-NAME
(n = 6) was superfused during blood perfusion, and the
vessels were recannulated 15 min after the superfusate was changed. In
those vessels (pipette and blood perfused, Figs. 4 and 5),
L-NAME led to an increase in
Lp from control values (Lpcontrol = 1.4 ± 0.2 × 107
cm · s1 · cmH2O1,
Lptest/Lpcontrol = 1.78 ± 0.16, P < 0.01), whereas
D-NAME was without effect
(Lpcontrol = 1.8 ± 0.4 × 107
cm · s1 · cmH2O1,
Lptest/Lpcontrol = 0.92 ± 0.04) (Fig. 4). To control for temporal changes in
Lp during exposure to L-NAME, we
exposed another group of vessels (n = 7) to
L-NAME for 15 min before beginning test measures of Lp without removing the pipette from the
microvessel. In those vessels, exposure to L-NAME led to a
reduction in Lp
(Lpcontrol = 2.6 ± 0.2 × 107
cm · s1 · cmH2O1,
Lptest/Lpcontrol = 0.50 ± 0.06, P < 0.05). The time course of the
responses to L-NAME in vessels with and without exposure to
blood is shown in Fig. 2B; the net response is illustrated
in Figs. 4 and 5. Whereas the number of adherent leukocytes per 100 µm in vessels exposed to L-NAME (5.1 ± 2.5, mean ± SE) tended to be greater than that in vessels exposed to
D-NAME (2.9 ± 0.8), the difference did not reach
statistical significance (P = 0.3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The main finding of this study is that one index of microvascular permeability, venular Lp, was modified acutely by the NOS inhibitor L-NAME. Importantly, the direction of the response differed according to the presence of blood-borne constituents in the vessels during L-NAME exposure.
Control Values
The control values of rat venule Lp reported in this study are similar to those reported by Kendall and Michel (13) using the same model. The frequency distribution shown in Fig. 1 shows that the distribution of values is not described by a normal distribution. The distribution is similar to those of frog mesenteric capillaries (6) and capillary filtration coefficient values in perfused mammalian hindlimbs (29). The reasons for the shape of the frequency distribution are not clear. Hargrave et al. (6) reported that frog capillary Lp values are normalized with a fourth-root transformation. Whether the shape of the distribution is due to a normal distribution of pore dimensions (of circular cross section, with resistance inversely proportional to the fourth power of the radius), as theorized by Pappenheimer et al. (29), remains to be determined. Regardless of the underlying mechanism, nonparametric statistics most appropriately describe this parameter.Influence of NOS Inhibition
In venules exposed to physiological salt solution (PSS) and protein, but in the absence of other elements contained in whole blood, exposure to L-NAME enhanced the vascular barrier properties, as evidenced by a nearly 50% reduction in permeability from control levels. The data support the conclusion that the responses were specific to NOS inhibition, because the inert enantiomer D-NAME was without effect on Lp. Furthermore, L-arginine but not D-arginine prevented the reduction in Lp by L-NAME. In fact, during exposure to L-NAME and L-arginine, Lp increased above control values. This finding is intriguing because endothelial cell NO production has been reported to depend little on extracellular arginine availability (28). Some investigators, though, have noted increases in NO production by extracellular arginine despite high cellular arginine content, leading to coining of the term "arginine paradox" (3). Substrate limitations due to colocalization of endothelial cell NOS and the arginine transporter cationic amino acid transporter 1 in endothelial caveolae have been proposed as a possible mechanism to account for this paradoxical phenomenon (20). However, in the absence of L-NAME, L-arginine did not influence venular Lp. Notably, Yuan et al. (40) described a similar effect of L-arginine on solute permeability of pig coronary venules: no effect on resting permeability but a 2.5-fold increase in permeability above control values after exposure to a NOS inhibitor. This finding may be attributed to enhanced NO release due to restoration of NO synthesis following NOS inhibition, as implied by Yuan et al. (40).In venules in which blood flow resumed during the experiment, L-NAME led to a 78% increase in Lp, in contrast to the 50% decrease in Lp in venules perfused only with PSS and protein. The increase in permeability was not due solely to mechanical stimulation by recannulation of vessels after blood perfusion because substitution of D-NAME for L-NAME in these protocols was without effect on Lp. These findings support the conclusion that NO has a dual effect on microvascular permeability: a direct influence on the vascular barrier, leading to increases in volume flux, and a second indirect effect mediated by blood elements, resulting in decreases in volume flux.
Leukocytes might be the blood-borne elements responsible for the secondary effect of NO on permeability. Leukocytes are associated with inflammatory changes in permeability, because depletion of circulating leukocytes abolishes the increases in permeability by various agonists (36). Adhesion to vascular endothelium is believed to be necessary for leukocytes to exert a permeability effect, possibly through adhesion-dependent functions such as emigration and superoxide production (15). Furthermore, L-NAME has been reported to increase leukocyte adhesion in blood-perfused rat mesenteric venules (17, 31). However, a direct effect of adherent leukocytes on the venules per se did not appear to account for the findings in this study, because the number of adherent leukocytes in the vessel segments used for assessment of Lp was not different between the L-NAME and D-NAME groups. Whether downstream leukocyte adhesion alone accounts for this observation (via a communicated response), as theorized by Harris (7), or whether additional blood-borne elements account for the L-NAME-induced increases in permeability remains to be determined in future studies.
Other blood-borne elements that might account for these findings are platelets. Platelet aggregates have been described at the sites of inflammatory changes in rat mesenteric venules (1, 39), and platelet granules contain various proinflammatory agents (27) associated with increases in microvascular permeability. Because NO inhibits platelet aggregation (24), it is conceivable that platelets may account for the increased permeability in vessels exposed to L-NAME in the presence of blood perfusion. Regardless of the blood-borne element involved in the secondary actions of NO on permeability, our study suggests that endogenous NO plays an important role in the regulation of basal hydraulic conductivity in the intact vasculature.
The mechanisms responsible for changes in Lp by NOS inhibition remain elusive. Microvascular volume flux occurs primarily through water-filled pathways, presumably the interendothelial cell junctions as well as several transendothelial pathways (reviewed in Ref. 22). We theorize that NOS inhibition alters the geometry of these pathways, thereby leading to decreases in volume flux. This may be consequent to NO-mediated actions on one of the cellular components of the venular wall, endothelial cells, pericytes, or vascular smooth muscle. Endothelial cells possess the ability to change shape in vivo and in vitro (25, 30). Cultured endothelial cells have been reported to change shape when exposed to an NO donor, sodium nitroprusside (25). Because endothelial cells possess soluble as well as particulate guanylyl cyclase (18), an increase in NO may, in an autocrine manner, modify endothelial cell geometry, thereby altering the dimensions of the volume flux pathways. Although the role of pericytes, contractile cells lying in close apposition to microvascular endothelial cells including rat mesenteric venules (12), in regulation of permeability is poorly understood, rat mesangial pericytes also change shape in response to NO donors (33). The role, if any, of vascular smooth muscle in regulation of venular hydraulic conductivity has not been studied.
Comparison With Other Studies
The reduction of Lp by L-NAME in pipette-perfused venules is consistent with our previous report that superfusion of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) decreased frog mesenteric capillary Lp (32). The similarities in Lp responses to NOS inhibitors between frogs and rats suggest that the basic mechanisms responsible for regulation of volume flux are conserved among animal species. These findings are also consistent with data from Yuan et al. (40) showing that L-NMMA decreased permeability coefficients to albumin in porcine coronary venules. He et al. (9) reported that perfusion with L-NMMA and L-NAME increased frog capillary Lp transiently; over longer times, they inhibited the increases in Lp induced by ionomycin and ATP. Thus the authors suggested that basal NO release and stimulated NO release have opposite effects on permeability, and they implied that decreases in permeability by NOS inhibitors would occur primarily in leakier vessels with higher basal permeability. The data from the present study argue against that postulate because, in two groups of venules with similar control values of hydraulic conductivity, the presence or absence of blood-borne constituents influenced the response to L-NAME (see Fig. 4).The reductions in Lp by L-NAME
described in this study were derived from pipette-perfused vessels
isolated functionally from the remainder of the circulation. This model
allows for the study of the direct influence of NOS inhibitors on
barrier permeability properties independent of effects mediated by
other components of blood. By using the method described by He et al.
(10) and allowing blood flow to come back into contact
with the venule segment during exposure to L-NAME, we were
able to distinguish direct vascular effects of test agents from
indirect effects mediated by blood-borne elements. The increases in
Lp by L-NAME in vessels in which
blood flow resumed are consistent with increases in permeability by NOS
inhibitors in blood-perfused experiments (7, 14). The
opposing effects of L-NAME dependent on the presence of
blood-borne elements reported here are consistent with data reported by
Harris (7) in rat mesenteric capillaries. In that study,
104 M L-NAME increased capillary filtration
by 66% from basal levels in normal animals, although it decreased
filtration by ~50% in neutropenic animals or when leukocyte adhesion
was inhibited. Notably, neutrophil adhesion did not occur in the
capillaries in which filtration was measured. Thus Harris proposed a
communicated response between leukocyte adherence downstream and
increased capillary filtration upstream. Although differences in
leukocyte adherence in the venule segments studied were not detected in this study, we cannot exclude a contribution of leukocyte adhesion downstream to the increase in permeability by L-NAME in the
blood-perfused experiments. Kubes and Granger (14)
reported that L-NAME increased vascular protein clearance
in blood-perfused feline intestine and that inhibition of leukocyte
adhesion attenuated the increases in protein clearance. On the basis of
those data, the authors proposed that the increases in protein
clearance by L-NAME were due to both leukocyte-dependent
and -independent effects. Leukocyte-independent actions of NOS
inhibitors that may influence permeability include mast cell activation
(4) and changes in oxidation potential (34),
among others. The interaction between leukocyte-dependent and
-independent mechanisms in regulation of microvascular responses to NOS
inhibitors remains to be elucidated.
Summary and Conclusions
In this study, we report that the NOS inhibitor L-NAME has differential effects on venular hydraulic conductivity, dependent on the presence of blood perfusion. L-NAME had a direct effect on the vascular barrier, leading to decreases in Lp, and an indirect effect mediated by yet to be identified constituents of blood, leading to increases in Lp. The dual effects of L-NAME on Lp may resolve partially some of the conflicting reports in the literature of the influence of NO on permeability. These findings support a role of endogenous NO release in regulation of basal microvascular permeability in the intact microvasculature, with a net response dependent on the integration of direct vascular effects and indirect effects mediated by blood-borne elements.| |
ACKNOWLEDGEMENTS |
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We thank Dr. Li Ping Ji and Susan Bingaman for superb technical assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants K08 HL-03738 (to R. E. Rumbaut), P01 HL-52490, and R37 HL-42528 (to V. H. Huxley) and by a grant from the American Heart Association (to R. E. Rumbaut).
Present address of R. E. Rumbaut: Baylor College of Medicine and Houston VA Medical Center, Pulmonary and Critical Care (111i), 2002 Holcombe Blvd., Houston, TX 77030.
Address for reprint requests and other correspondence: V. H. Huxley, Dept. of Physiology, Univ. of Missouri-Columbia, MA 415, Medical Sciences Bldg., Columbia, MO 65212 (E-mail: HuxleyV{at}health.missouri.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4 February 2000; accepted in final form 30 May 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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1.
Baldwin, AL,
and
Thurston G.
Changes in endothelial actin cytoskeleton in venules with time after histamine treatment.
Am J Physiol Heart Circ Physiol
269:
H1528-H1537,
1995
2.
Curry, FE,
Huxley VH,
and
Sarelius IH.
Techniques in the microcirculation: measurement of permeability, pressure and flow.
In: Techniques in the Life Sciences. County Clare, Ireland: Elsevier Scientific, 1983.
3.
Förstermann, U,
Closs EI,
Pollock JS,
Nakane M,
Schwarz P,
and
Gath I.
Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions.
Hypertension
23:
1121-1131,
1994
4.
Gaboury, JP,
Niu XF,
and
Kubes P.
Nitric oxide inhibits numerous features of mast cell-induced inflammation.
Circulation
93:
318-326,
1996
5.
Gore, RW,
and
Baldwin AL.
Intestinal and mesenteric preparations for microvascular studies.
In: Microcirculatory Technology, edited by Baker CH,
and Nastuk WL.. Orlando, FL: Academic, 1986.
6.
Hargrave, RW,
Huxley VH,
and
Thipakorn B.
Seasonal variations of capillary hydraulic conductivity and volume status.
Am J Physiol Regulatory Integrative Comp Physiol
268:
R468-R474,
1995
7.
Harris, NR.
Opposing effects of L-NAME on capillary filtration rate in the presence or absence of neutrophils.
Am J Physiol Gastrointest Liver Physiol
272:
G1320-G1325,
1997.
8.
He, P,
and
Curry FE.
Depolarization modulates endothelial cell calcium influx and microvessel permeability.
Am J Physiol Heart Circ Physiol
261:
H1246-H1254,
1991
9.
He, P,
Liu B,
and
Curry FE.
Effect of nitric oxide synthase inhibitors on endothelial [Ca2+]i and microvessel permeability.
Am J Physiol Heart Circ Physiol
272:
H176-H185,
1997
10.
He, P,
Wang J,
and
Zeng M.
Leukocyte adhesion and microvessel permeability.
Am J Physiol Heart Circ Physiol
278:
H1686-H1694,
2000
11.
Huxley, VH.
Physiologic regulation of capillary permeability.
J Reconstr Microsurg
4:
341-346,
1988[Medline].
12.
Joyce, NC,
DeCamilli P,
and
Boyles J.
Pericytes, like vascular smooth muscle cells, are immunocytochemically positive for cyclic GMP-dependent protein kinase.
Microvasc Res
28:
206-219,
1984[Web of Science][Medline].
13.
Kendall, S,
and
Michel CC.
The measurement of permeability in single rat venules using the red cell microperfusion technique.
Exp Physiol
80:
359-372,
1995[Abstract].
14.
Kubes, P,
and
Granger DN.
Nitric oxide modulates microvascular permeability.
Am J Physiol Heart Circ Physiol
262:
H611-H615,
1992
15.
Kubes, P,
Grisham MB,
Barrowman JA,
Gaginella T,
and
Granger DN.
Leukocyte-induced vascular protein leakage in cat mesentery.
Am J Physiol Heart Circ Physiol
261:
H1872-H1879,
1991
16.
Kubes, P,
Suzuki M,
and
Granger DN.
Nitric oxide: an endogenous modulator of leukocyte adhesion.
Proc Natl Acad Sci USA
88:
4651-4655,
1991
17.
Kurose, I,
Kubes P,
Wolf R,
Anderson DC,
Paulson J,
Miyasaka M,
and
Granger DN.
Inhibition of nitric oxide production. Mechanisms of vascular albumin leakage.
Circ Res
73:
164-171,
1993[Abstract].
18.
Martin, W,
White DG,
and
Henderson AH.
Endothelium-derived relaxing factor and atriopeptin II elevate cyclic GMP levels in pig aortic endothelial cells.
Br J Pharmacol
93:
229-239,
1988[Web of Science][Medline].
19.
Mason, JC.
Studies on the Permeability of Single Capillaries. (PhD thesis). Oxford, UK: Oxford Univ, 1976.
20.
McDonald, KK,
Zharikov S,
Block ER,
and
Kilberg MS.
A caveolar complex between the cationic amino acid transporter 1 and endothelial nitric-oxide synthase may explain the "arginine paradox".
J Biol Chem
272:
31213-31216,
1997
21.
Meyer, DJ, Jr,
and
Huxley VH.
Capillary hydraulic conductivity is elevated by cGMP-dependent vasodilators.
Circ Res
70:
382-391,
1992
22.
Michel, CC,
and
Curry FE.
Microvascular permeability.
Physiol Rev
79:
703-761,
1999
23.
Michel, CC,
Mason JC,
Curry FE,
Tooke JE,
and
Hunter PJ.
A development of the Landis technique for measuring the filtration coefficient of individual capillaries in the frog mesentery.
Q J Exp Physiol
59:
283-309,
1974
24.
Moncada, S,
Palmer RM,
and
Higgs EA.
Nitric oxide: physiology, pathophysiology, and pharmacology.
Pharmacol Rev
43:
109-142,
1991[Web of Science][Medline].
25.
Morel, NM,
Dodge AB,
Patton WF,
Herman IM,
Hechtman HB,
and
Shepro D.
Pulmonary microvascular endothelial cell contractility on silicone rubber substrate.
J Cell Physiol
141:
653-659,
1989[Web of Science][Medline].
26.
Neal, CR,
and
Michel CC.
Transcellular gaps in microvascular walls of frog and rat when permeability is increased by perfusion with the ionophore A23187.
J Physiol (Lond)
488:
427-437,
1995
27.
Packham, MA.
Role of platelets in thrombosis and hemostasis.
Can J Physiol Pharmacol
72:
278-284,
1994[Web of Science][Medline].
28.
Palmer, RM,
Ashton DS,
and
Moncada S.
Vascular endothelial cells synthesize nitric oxide from L-arginine.
Nature
333:
664-666,
1988[Medline].
29.
Pappenheimer, JR,
Renkin EM,
and
Borrero LM.
Filtration, diffusion and molecular sieving through peripheral capillary membranes. A contribution to the pore theory of capillary permeability.
Am J Physiol
167:
13-46,
1951.
30.
Ragan, DM,
Schmidt EE,
MacDonald IC,
and
Groom AC.
Spontaneous cyclic contractions of the capillary wall in vivo, impeding red cell flow: a quantitative analysis. Evidence for endothelial contractility.
Microvasc Res
36:
13-30,
1988[Web of Science][Medline].
31.
Rumbaut, RE,
Harris NR,
Sial AJ,
Huxley VH,
and
Granger DN.
Leakage responses to L-NAME differ with the fluorescent dye used to label albumin.
Am J Physiol Heart Circ Physiol
276:
H333-H339,
1999
32.
Rumbaut, RE,
McKay MK,
and
Huxley VH.
Capillary hydraulic conductivity is decreased by nitric oxide synthase inhibition.
Am J Physiol Heart Circ Physiol
268:
H1856-H1861,
1995
33.
Shultz, PJ,
Schorer AE,
and
Raij L.
Effects of endothelium-derived relaxing factor and nitric oxide on rat mesangial cells.
Am J Physiol Renal Fluid Electrolyte Physiol
258:
F162-F167,
1990
34.
Suematsu, M,
Tamatani T,
Delano FA,
Miyasaka M,
Forrest M,
and
Suzuki H.
Microvascular oxidative stress preceding leukocyte activation elicited by in vivo nitric oxide suppression.
Am J Physiol Heart Circ Physiol
266:
H2410-H2415,
1994
35.
Tucker, VL,
and
Huxley VH.
O2 modulation of single-vessel hydraulic conductance.
Am J Physiol Heart Circ Physiol
254:
H317-H323,
1988
36.
Wedmore, CV,
and
Williams TJ.
Control of vascular permeability by polymorphonuclear leukocytes in inflammation.
Nature
289:
646-650,
1981[Medline].
37.
Williams, DA.
Network assessment of capillary hydraulic conductivity after abrupt changes in fluid shear stress.
Microvasc Res
57:
107-117,
1999[Web of Science][Medline].
38.
Williams, DA,
and
Huxley VH.
Bradykinin-induced elevations of hydraulic conductivity display spatial and temporal variations in frog capillaries.
Am J Physiol Heart Circ Physiol
264:
H1575-H1581,
1993
39.
Withers, GD,
Kubes P,
Ibbotson G,
and
Scott RB.
Anaphylaxis-induced mesenteric vascular permeability, granulocyte adhesion, and platelet aggregates in rat.
Am J Physiol Heart Circ Physiol
275:
H274-H284,
1998
40.
Yuan, Y,
Granger HJ,
Zawieja DC,
and
Chilian WM.
Flow modulates coronary venular permeability by a nitric oxide-related mechanism.
Am J Physiol Heart Circ Physiol
263:
H641-H646,
1992
41.
Zhang, RS,
and
Huxley VH.
Control of capillary hydraulic conductivity via membrane potential-dependent changes in Ca2+ influx.
Am J Physiol Heart Circ Physiol
262:
H144-H148,
1992
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, n = 10) and
10
, n = 9) on
Lp of pipette perfused vessels. B:
influence of 15 min of exposure to test solutions before test
measurements of Lp were obtained. Two groups
were perfused with blood during exposure to either L-NAME
(
, n = 10) or D-NAME
(
, n = 6), and another group was
perfused with protein in bicarbonate-buffered saline (BBS) during
L-NAME exposure (
, n = 7).
