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Vol. 83, Issue 6, 1941-1946, December 1997
1 Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, der Westfälischen Wilhelms-Universität, Münster, Germany; and 2 Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas 77555-1091
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
FOOTNOTES
REFERENCES
ABSTRACT 
Hinder, Frank, Michael Booke, Lillian D. Traber, and Daniel
L. Traber. Nitric oxide and endothelial permeability.
J. Appl. Physiol. 83(6):
1941-1946, 1997.
Nitric oxide synthase inhibition reverses
systemic vasodilation during sepsis but may increase endothelial
permeability. To assess adverse effects on the pulmonary vasculature,
12 sheep were chronically instrumented with lung lymph fistulas and
hydraulic pulmonary venous occluders. Escherichia coli endotoxin (lipopolysaccharide; 10 ng · kg
1 · min1)
was continuously infused for 32 h. After 24 h, six animals received 25 mg/kg of N
-nitro-L-arginine
methyl ester (L-NAME), and six
received saline. All sheep developed a hyperdynamic circulatory
response and elevated lymph flows by 24 h of lipopolysaccharide
infusion. L-NAME reversed systemic vasodilation, increased pre- and postcapillary pulmonary vascular resistance index, pulmonary arterial pressure, and,
transiently, effective pulmonary capillary pressure. Lung lymph flows
were not different between groups at 24 h or thereafter. Calculated as
changes from baseline, however, lung lymph flow was higher in the
L-NAME group than in the control
animals, with a trend toward lower lymph-to-plasma protein
concentration ratio at 25 h. Permeability analysis at 32 h by the
venous occlusion technique showed normal reflection coefficients and
elevated filtration coefficients without differences between groups.
Reversal by L-NAME of the
systemic vasodilation during endotoxemia was associated with high
pulmonary vascular resistance without evidence of impaired pulmonary
endothelial barrier function.
nitric oxide synthase inhibition; lung; hyperdynamic sepsis; lung
edema; vasodilation; pulmonary endothelial
permeability
INTRODUCTION NITRIC OXIDE (NO) produced by the different isoforms of
NO synthase (NOS) accounts for most of the activity of the
endothelium-derived relaxing factor and is a key mediator in the
regulation of blood flow under many physiological conditions (33, 34).
During sepsis, however, an overproduction of NO by the inducible NOS (iNOS) may occur and result in septic vasodilation and shock. iNOS is
synthetized in high quantities in endothelial cells (23), vascular
smooth muscle cells (1), and macrophages in response to a variety of
stimuli during sepsis (19). NOS inhibitors have been administered both
to septic patients (6, 27) and in the hyperdynamic animal model of
sepsis (20, 21, 25, 26), characterized by a low systemic vascular
resistance and an elevated cardiac output (CO), to reverse the
sepsis-associated systemic vasodilation.
Blockade of NOS, however, may elicit serious side effects on
microvascular permeability. Granulocytes, adhering to the endothelium of postcapillary intestinal venules, emigrated from the vessel when a
NOS inhibitor was administered (17). Furthermore, inhibition of NOS led
to an increase in both endothelial and epithelial intestinal permeability in normal cats (13, 15), and an increase in permeability due to ischemia-reperfusion injury was attenuated when a NO donor compound was infused (14).
Other studies indicated that NO itself may be detrimental regarding
microvascular barrier function (2, 3, 10, 12, 28, 29). The generation
of strong oxidants like peroxynitrite from the reaction of NO with
superoxide may cause or aggravate endothelial and epithelial damage (2,
28, 29). Recently, evidence has been found for nitrogen-derived
oxidants in human pulmonary tissue after acute lung injury (12). The
administration of NOS inhibitors limited vascular permeability in
endotoxin-induced gut mucosal injury in rats (3) and prevented
permeability changes in lung alveolar injury from smoke inhalation
(10).
Yet to be defined is the role endogenous NO may play in the maintenance
of an intact pulmonary endothelial barrier function when NOS inhibitors
are administered during a state of septic vasodilation.
This study was designed to evaluate the effect of NOS inhibition on
lung microvascular permeability in a model of hyperdynamic ovine
endotoxemia in awake spontaneously breathing sheep, where factors like
ventilation that may alter permeability independant of NO are not
present. We hypothesized that pulmonary endothelial permeability to
protein would increase after inhibition of NOS.
METHODS
|
(1) |
|
(2) |
l) is presented both in milliliters per hour and
as changes from baseline. The lymph was then transferred to heparinized
sample tubes. Lymph (Clp) and plasma (Cpp) protein concentrations were determined by using the biuret technique. The colloid osmotic pressures
of lymph (
l) and plasma
(p) were directly measured through the semipermeable membrane of a colloid osmometer (model 4100, Wescor, Logan, UT) with a pore diameter of 0.0004 µm.
Permeability analysis.
The reflection coefficient to protein (
) was determined by using the
pulmonary venous occlusion technique described by Isago et al. (9). In
short, all pulmonary venous occluders were inflated with saline to
increase Pmv, resulting in a rising l with Clp decreasing at a stable Cpp. During hydraulic occlusion, all variables were measured every 30 min. The occlusion was maintained until the rise
in l was not accompanied by a further
decline in Clp/Cpp but was maintained for at least 2 h. In this state,
Clp/Cpp is assumed to be filtration independent and can be used to
calculate the reflection coefficient to protein by using the following
equation
|
(3) |
![<IT>J</IT><SUB>v</SUB> = <IT>K</IT><SUB>f</SUB>[(Pmv − Pi) − &sfgr;(&pgr;<SUB>p</SUB> − &pgr;<SUB>i</SUB>)]](/content/vol83/issue6/fulltext/1941/img004.gif)
|
(4) |
l equals
Jv for a
particular region of the lung; 2)
the interstitial oncotic pressure
i equals
l; and
3) the interstitial hydrostatic
pressure (Pi) is stable and
equals the mean alveolar pressure = 0 mmHg.
The filtration coefficient
(Kf) was
calculated by using Eq. 5 after
translation of Eq. 4 and changing of
the variables according to assumptions
1-3
![<IT>K</IT><SUB>f</SUB> = <A><AC>Q</AC><AC>˙</AC></A>l/[Pmv − &sfgr;(&pgr;<SUB>p</SUB> − &pgr;<SUB>l</SUB>)]](/content/vol83/issue6/fulltext/1941/img005.gif)
|
(5) |
l and Clp had normalized again.
Experimental protocol.
The animals were randomly assigned to one of two groups. After baseline
data had been collected, all sheep were started on a continuous
infusion of Escherichia coli endotoxin
(10 ng · kg1 · min1)
in NaCl (0.9%), which was maintained for 35 h. After 24 h of endotoxemia, six animals received a bolus injection of the NOS inhibitor L-NAME in NaCl
(0.9%), whereas the other group (control, n = 6) was given an
equivalent volume of saline.
The experiments were accomplished according to the guidelines of the
National Institutes of Health and the American Physiological Society
and were approved by the Animal Care and Use Committee of The
University of Texas Medical Branch.
Data analysis.
Results are presented as means ± SE. The data were analyzed by
analysis of variance for repeated measures with post hoc
Scheffé's F-test for
differences from 0 to 24 h. Analysis of variance for factorial analysis
was applied to test for statistical differences between groups.
Differences were regarded as statistically significant when
P < 0.05.
RESULTS
Both groups of sheep developed a hyperdynamic response characterized by
a significant decrease in SVRI and an elevated CI after 24 h of
endotoxemia (Fig. 1). Mean arterial
pressure (MAP) showed a trend to lower values than at baseline at 24 h.
These changes in systemic circulatory variables remained stable in the control group until 32 h. Administration of the NOS inhibitor L-NAME reversed the pronounced
vasodilation. SVRI and MAP rose to values that were even higher than at
baseline and at 24 h and higher than in the control group 1 h after
L-NAME had been given (P < 0.05). At 32 h, neither SVRI nor CI nor MAP
of the animals treated with
L-NAME was different from
baseline values, but they were still significantly different from 24-h
values.
-nitro-L-arginine methyl ester
(L-NAME; 25 mg/kg) after 24 h of endotoxemia, and the other group was given saline (control).
* P < 0.05 vs. 0 h.
P < 0.05 vs. 24 h.
P < 0.05 vs. control group.
PVRI was not changed during the hyperdynamic phase of endotoxemia in
the control animals (Fig. 2). After
inhibition of NOS, PVRI increased and remained elevated until 32 h.
PVRI was also analyzed for its distribution between the pre- and
postcapillary pulmonary vascular bed (Table
1). Precapillary PVRI accounted for
approximately two-thirds of the total PVRI in both groups at baseline.
Precapillary PVRI of the control group showed a trend to higher levels
than at baseline at 24 and 25 h and was significantly elevated at 32 h
(Fig. 2). Postcapillary PVRI of these animals did not change
significantly at the observed time points. Precapillary PVRI had
markedly increased 1 h after administration of
L-NAME (P < 0.05 vs. 0-h, 24-h, and control
values) and remained significantly elevated until 32 h. The
distribution of PVRI did not change significantly during the marked
increase in PVRI (Table 1). Accordingly, postcapillary PVRI rose 1 h
after the administration of
L-NAME
(P < 0.05 vs. 0- and 24-h values;
Fig. 2) and was still higher than at baseline at 32 h.
P < 0.05 vs. 24 h.
P < 0.05 vs. control
group.
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PAP increased during endotoxemia in both groups
(P < 0.05) and remained
elevated in the control group throughout the experimental period (Fig.
3). PAP increased significantly 1 h after administration ofL-NAME
(P < 0.05 vs. 0-h, 24-h, and control
values). Pmv was elevated in the
L-NAME-treated animals at 25 h
compared with 0 and 24 h. Both PAP and Pmv had returned to control
group levels by 32 h. Neither PCWP nor LAP changed significantly over
time (Table 1), nor were there significant differences between
experimental groups in these variables.
P < 0.05 vs. 24 h.
P < 0.05 vs. control
group.
l was different between groups, both when the
baseline reflection coefficient was determined (control group: 7.9 ± 1.6 ml/h vs. L-NAME group:
4.6 ± 1.1 ml/h) and 48 h later, before the infusion of endotoxin
was begun (control group: 7.6 ± 1.1 ml/h vs.
L-NAME group: 3.5 ± 0.7 ml/h) (Fig. 4). Clp/Cpp was almost equal
between the two groups at these time points.
l;
A), increase of l × baseline (B), and ratio of
lymph and plasma protein concentrations (Clp/Cpp;
C) during 32 h of continuous
endotoxin infusion. Groups are described as in Fig. 1.
* P < 0.05 vs. 0 h.
P < 0.05 vs control
group.
l was elevated at 24, 25, and 32 h in both groups
(Fig. 4) without differences between the two groups. However, if
l was calculated as increase from baseline
(lrel),
lrel rose
significantly after administration of
L-NAME to a level higher than in
the control group at 25 h (P < 0.01). The values of the control and
L-NAME-treated animals were no
longer significantly different 32 h after the infusion of
lipopolysaccharide had begun. Clp/Cpp decreased by 24 h when
l was elevated and remained low for the rest of the study period (P < 0.05 vs. 0 h
values in both groups). Clp/Cpp values in the
L-NAME group showed a trend to
lower values than in the control at 25 h. Clp/Cpp values of both groups
were similar again at 32 h.
The osmotic reflection coefficient to protein was at baseline level
after 32 h of endotoxemia (Fig. 5). There
was no difference between groups at either baseline or after 32 h.
Filtration coefficients of both groups were elevated
(P < 0.05). Again, there was no
difference between groups.
DISCUSSION
l differed between groups at the two baseline
measurements that were 48 h apart. Because
l was stable and concomitant Clp/Cpp was
practically equal in both groups, the higher l is likely to have resulted from causes such as different lengths of the
lymphatic catheters, different heights of the catheter outlet relative
to the point of its insertion, and different volumes of lung drained.
If the elevated l had been due to a real increase in
fluid filtration, lymph protein would have been washed down, which
obviously was not the case. The trend to higher filtration coefficients
in the control group can be explained by the fact that this variable is
calculated by an equation that contains l.
Finally, the baseline values in both groups were well within the limits
of published baseline values in recent investigations (5, 24). To
unmask possible effects of
L-NAME, which may have been
hidden otherwise, l was presented both as raw data and as increases from baseline (i.e.,
lrel).
A high l indicated an elevated rate of transvascular
fluid flux at 24 h. l did not differ between both
groups after the administration of
L-NAME.
lrel in the
L-NAME-treated sheep, however, surpassed
those of the control animals at 25 h, but inhibition of the NOS did not
affect the reflection coefficient to protein or filtration coefficent
at 32 h.
The increase in
lrel occurred
during a period when Pmv was elevated. Both variables returned to their
former levels thereafter. Moreover, inhibition of NOS has been shown to
prevent the negative chronotropic and inotropic effects that NO has on
the spontaneous contraction of isolated lymphatics (36). Therefore, a
more efficient lymphatic pump may have contributed to the higher
lrel in the L-NAME-treated animals. The
higher lrel
compared with the control group was associated with a trend of Clp/Cpp
to decline in the L-NAME group.
The fact that Clp/Cpp tended to decrease during the elevated
lrel suggests a washdown effect on the
lymph protein.
The venous occlusion technique is generally accepted as a method that
allows for the evaluation of the lung microvascular permeability to
protein in conscious animals. For interpretation of our data, several
issues must be considered. Studies that had shown an increase in
systemic microvascular permeability to protein after the administration
of L-NAME in normal cats
reported that the changes in permeability occurred within the first
hour after inhibition of NOS and were associated with a fourfold
increase in l (15). We did not occlude
the pulmonary veins before 8 h after the administration of
L-NAME but followed
l and Clp/Cpp during the 8 h period. Thus the lymph
data represent early changes in transvascular fluid flux, whereas the
reflection and filtration coefficients represent late changes in
pulmonary microvascular permeability.
Even if the venous occlusion technique was not performed before 8 h
after L-NAME had been given, it
can be concluded that, if an increase in microvascular permeability to
small particles had occurred early after
L-NAME, it would have been of
minor impact. Our data are consistent with those of Kavanagh et al.
(11), which did not find an increase in the filtration coefficient when a NOS inhibitor was added to the buffer that perfused an isolated rabbit lung with oxidant-induced injury.
Still, a clear picture regarding the role of endogenous NO in the
maintenance of an intact barrier function under physiological and
pathological conditions cannot be drawn. There are data supporting both
protective (13-16, 35) and detrimental effects (2, 3, 10, 12, 28,
29) of NO.
In conclusion, administration of NOS inhibitor reversed the
hyperdynamic response to the continuous infusion of endotoxin. Inhibition of NOS was associated with a transient increase in Pmv and
lrel. There was
no evidence of an elevated lung microvascular permeability to protein
or a further increase in filtration coefficient after administration of
L-NAME in this model. Further
studies must be performed to elucidate the impact of different species and models on the role of NO in the maintenance of endothelial barrier
function.
FOOTNOTES
Address for reprint requests: D. L. Traber, The Univ. of Texas Medical Branch, Dept. of Anesthesiology, Investigational Intensive Care Unit, 610 Texas Ave., Galveston, TX 77555-1091 (E-mail: traber{at}beach.utmb.edu).
Received 20 August 1996; accepted in final form 25 July 1997.
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