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Department of Medical Sciences, Clinical Physiology, University Hospital, SE-751 85 Uppsala, Sweden
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study
addressed the possible role of cyclooxygenase (COX) and its products in
the rebound response to inhaled nitric oxide (INO). Anesthetized,
mechanically ventilated piglets were exposed to endotoxin alone,
endotoxin combined with INO, or endotoxin with INO plus the COX
inhibitor diclofenac (3 mg/kg iv) (n = 8 piglets/group). A control group of healthy pigs (n = 6)
was also studied. Measurements were made of blood gases, hemodynamic
parameters, lung tissue COX expression, and plasma concentrations of
thromboxane B2 (TxB2), PGF2
, and
6-keto-PGF1. Endotoxin increased lung inducible COX
(COX-2) expression and circulating prostanoids concentrations.
Inhalation of NO during endotoxemia increased the constitutive COX
(COX-1) expression, and the circulating TxB2 and
PGF2 increased further after INO withdrawal. The
combination of COX inhibitor with INO blocked all these changes and
eliminated the rebound reaction to INO withdrawal, which otherwise was
seen in endotoxemic piglets given INO only. We conclude that the
rebound response to INO discontinuation is related to COX products.
nitric oxide inhalation; prostanoids
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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INHALED NITRIC OXIDE (INO) is a selective pulmonary vasodilator in the treatment of pulmonary hypertension. However, life-threatening hemodynamic instability, reduced oxygenation, and even death have been observed during attempts to withdraw INO (1, 10, 17). These phenomena are referred to as the rebound response to INO withdrawal. Stepwise reduction of the NO dose implies prolongation of the NO therapy and may still not eliminate the rebound response (10).
The mechanisms responsible for the rebound response are not fully understood. NO stimulates the release of soluble guanylate cyclase from the tissues, with a consequent increase in cGMP. INO reduces the endogenous NO production as a negative feedback mechanism, and this mechanism is assumed to be related to the rebound reaction to INO withdrawal (1, 2, 9). We have previously found that the production and/or release of the vasoconstrictor peptide endothelin-1 (ET-1) and possibly of other vasoconstrictors is also related to the rebound, and this may be even more important than the downregulation of endogenous NO production by INO (5).
ET-1 and some prostanoids, in particular thromboxane A2
(TxA2) and PGF2, are important
vasoconstriction mediators in primary and secondary pulmonary
hypertension (6, 22, 23). In addition, ET-1-stimulated
secondary release of TxA2 is one of the main modes of
signal transduction in ET-1-induced vasoconstriction (21).
PGI2 and TxA2, and PGF2, are
important mutually antagonistic vasodilator and vasoconstrictor
products, respectively, of arachidonic acid. They are synthesized via a
cyclooxygenase (COX)-dependent pathway. A PGI2 analog has
been reported to mitigate the rebound response to INO withdrawal in a
case study (14).
On the basis of these observations, we hypothesized that the rebound
response to INO withdrawal is related to COX-derived vasoconstrictor
products such as TxA2 and PGF2. The purpose of the present study was to determine whether a COX inhibitor could
prevent a rebound reaction to INO withdrawal in a porcine endotoxin
shock model.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal Preparation
The Animal Research Ethics Committee of Uppsala University approved the study. Thirty piglets of Swedish country breed, weighing 24-29 kg, were used. Anesthesia was induced with intramuscular atropine (0.04 mg/kg), tiletamine-zolazepam (6 mg/kg, Zoletid, Virbac Laboratories), and xylazine chloride (2.2 mg/kg, Rompun, Bayer) and maintained with a continuous infusion of a hypnotic, clormethiazole (400 mg/h, Heminevrin, Astra; Södertälje, Sweden), pancuronium (2 mg/h), and fentanyl (150 µg/h) (5). Prewarmed (38°C) isotonic saline (10-20 ml · kg
1 · h1)
was given intravenously in endotoxin-exposed piglets to prevent dehydration and maintain a stable intravascular volume; 5-10
ml · kg1 · h1
saline was given intravenously in the healthy controls. The animals were placed in the supine position for the remainder of the study.
After the induction of anesthesia, a tracheotomy was performed and a cuffed tracheal tube was inserted. Mechanical ventilation was provided in the volume-controlled mode (Servo 900 C, Siemens-Elema; Lund, Sweden) at a respiratory frequency of 21 ± 2 breaths/min, an inspiratory-to-expiratory ratio of 1:2, and an end-inspiratory pause of 5% of the respiratory cycle, with oxygen in nitrogen. The minute ventilation was adjusted to obtain an end-tidal CO2 tension of 33-45 mmHg (4.4-6.0 kPa) in the initial control situation and was then kept constant throughout the experiment. The mean tidal volume was 10 ± 1.4 ml/kg. A positive end-expiratory pressure of 5 cmH2O was applied. The inspired fraction of oxygen (FIO2) was 0.5. Further details are given in a previous study (5).
A triple-lumen balloon-tipped catheter (Swan Ganz No. 7F) was introduced into the pulmonary artery for blood sampling and pressure recording. The contralateral jugular vein and right carotid artery catheters were also introduced for pressure recording, blood sampling, and infusion. Mean arterial pressure, mean pulmonary arterial pressure (MPAP), heart rate (HR), central venous pressure, pulmonary capillary wedge pressure, and cardiac output (Qt) were recorded. For further details, see a previous report by our group (5).
Mixed venous and arterial blood samples were collected for blood gas
analysis (ABL 3, Radiometer; Copenhagen, Denmark) and determination of
oxygen saturation and hemoglobin concentration (OSM 3, Radiometer).
Hemoximeter data were corrected for pig blood. Blood samples (5 ml)
were also collected at the same time. The plasma was separated
immediately at 4°C and kept at 
70°C before biochemical analysis.
NO Administration
NO, 1,000 ppm in N2, was added to a mixture of O2-N2 and administered through the low-flow inlet of the ventilator. The inspired gas was passed through a canister containing soda lime to absorb any NO2. The inhaled NO was set to 30 ppm, and the concentration of inspired NO2 was always <0.5 ppm. The concentrations of inspired NO and NO2 were measured continuously by chemiluminescence (9841 NOx, Lear Siegler Measurement Controls; Englewood, CO) in the inspiratory limb of the ventilator tubing. FIO2 was checked after the addition of NO and kept stable at the pre-INO level.Protocol
Thirty minutes after surgery, baseline measurements of hemodynamic parameters were made and blood samples were drawn. Blood gas analysis was performed, and plasma was collected for subsequent biochemical analysis.In 24 animals, a septic model of acute lung injury was created. This
was achieved by an intravenous infusion of endotoxin (LPS,
Escherichia coli 0111:B4, Sigma; St. Louis, MO) at a dose of
25 µg · kg1 · h1
for 3 h, followed by a maintenance dose of 10 µg · kg1 · h1.
The hemodynamic and gas exchange responses were measured 30, 60, 120, 150, and 180 min after the start of the endotoxin infusion. To test the
effects of endotoxin and INO, and the potential protective effect of a
COX inhibitor against a rebound response after INO withdrawal, the
piglets were allocated to one of the following groups: 1)
endotoxin, 2) endotoxin + INO, or 3)
endotoxin + INO + COX inhibitor. In addition, another six
piglets were studied as healthy controls (group 4).
Group 1: endotoxin (n = 8). These animals received the endotoxin infusion at the dose mentioned above and mechanical ventilation as described above for all animals for a 5-h period, with intermittent recordings of hemodynamics, gas exchange, and blood sampling. This was done to check for the reaction to endotoxin per se.
Group 2: endotoxin + INO (n = 8).
After 3 h of endotoxin infusion, inhalation of NO (30 ppm) was
started as described above and maintained for 30 min (Fig. 1). Before INO was discontinued and 5, 10, 15, and 30 min after its withdrawal, hemodynamic parameters were
measured, and blood was sampled for gas exchange and biochemical
analyses. The purpose of this group was to check for the effectiveness
of INO per se and for any rebound reaction to INO withdrawal.
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Group 3: endotoxin + INO + COX inhibitor (n = 8). After ~150 min of endotoxin infusion, a nonselective COX inhibitor, diclofenac (Lot 117H0326, Sigma) in saline (3 mg/kg), was given as an intravenous injection (Fig. 1). Inhalation of NO (30 ppm) was started 30 min after the diclofenac injection, 3 h after the start of endotoxin infusion. The protocol was thus the same as in the endotoxin + INO group, except that the COX inhibitor diclofenac was given.
Diclofenac was chosen because it is effective, its action is rapid, and it inhibits both constitutive COX (COX-1) and inducible COX (COX-2). The dose of diclofenac was decided on the basis of our preliminary tests and a previous study by other authors (28).Group 4: healthy controls (n = 6). These animals did not receive endotoxin infusion, but otherwise the protocol was the same as in the endotoxin group.
Finally, all piglets were killed with an intravenous injection of KCl via the central venous catheter. A thoracotomy was performed, and a piece of lung tissue was cut off from the left middle lobe. The lung tissue samples were cut into blocks of ~0.5 × 0.5 × 0.3 cm, which were snap-frozen with liquid nitrogen and kept at70°C pending Western blot measurements. The total study time, including anesthesia, preparation, and baseline measurements, was ~7 h.
Lung Tissue COX Analysis
The total protein contents of the lung tissue was extracted by homogenization (UltraTurrax, Jenke and Kunkel, IKA Labortechnik; Staufen, Germany) in 5 vol of ice-cold 0.05 M Tris buffer (pH 7.4) containing 0.5 mM phenylmethylsulfonyl fluoride to inhibit proteolysis. The supernatant was collected and stored at70°C until analyzed.
The concentration of whole protein in the supernatant was determined by the method of Lowry, and the protein was then fractionated by SDS-PAGE and electrophoretically transferred to a nitrocellulose membrane. The blot was blocked with 5% BSA in Tris-buffered saline (TBS) at 4°C overnight. It was then incubated with anti-COX-1 (1:500, Catalog No. 160108, Cayman Chemical) and anti-COX-2 (1:1,000, Catalog No. 360120, Cayman Chemical) in TBS containing 1% BSA at 4°C overnight. After being washed with TBS five times, the blot was incubated for 1 h with horseradish peroxidase-conjugated goat anti-rabbit IgG (1:2,500 dilution, Vector Laboratories) for COX-1 and COX-2 detection.
The blot was then again washed five times in TBS, after which the antigen-antibody complex was detected on photographic film using enhanced chemiluminescence reagent (Amersham; Arlington Heights, IL). All the experiments were carried out three times, and the bands from each experiment were analyzed using the NIH Image 1.6 C program for statistical analysis.
Plasma Prostaglandin Analysis
TxA2 and PGI2 converted to their stable metabolites TxB2 and 6-keto-PGF1,
respectively, within a minute after they had been released. We
therefore measured plasma TxB2 and
6-keto-PGF1 as indicators of TxA2 and
PGI2 release. PGF2, TxB2, and
6-keto-PGF1 concentrations were measured with
commercially available enzyme immunoassay kits (prostaglandin
F2 EIA kit, 516011; thromboxane B2 EIA kit,
519031; and 6-keto-prostaglandin F1 EIA kit, 515211;
Cayman Chemical).
To ensure that all samples were free from organic solvents, the serum
was purified according to the instructions of Cayman Chemical before it
was added to the assay. Enzyme immunoassays were performed in duplicate
by mixing 50 µl purified sample with 50 µl tracer and 50 µl
antiserum on microplates. After 18 h of incubation, 200 µl
Ellman's reagent was added to start the enzymatic reaction, and the
adsorption of individual vials was measured 30 min later at 405 nm
using a photometry microplate reader (Thermo Max, Molecular Devices).
Concentrations of TxB2, PGF2, and 6-keto-PGF1 in the samples were estimated separately
from standard curves. The intra- and interassay coefficients of
variation were <10%.
Statistical Analysis
Means ± SD were calculated for all variables under all study conditions. Two-way ANOVA for repeated measurements on one factor was applied to disclose any differences within groups and also any differences between groups (endotoxin + INO + COX inhibitor group compared with endotoxin + INO group, and both compared with endotoxin and healthy control groups). The P values were corrected for multiple comparisons in the least-significance difference test, and the least-significant difference test was used for post hoc tests. Differences were regarded as significant at a P level of <0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Baseline Variables and Effects of Endotoxin-Induced Lung Damage
In the animals of the four groups, the baseline hemodynamics and arterial oxygenation were similar to those observed in healthy piglets and in previous experiments from our laboratory (5), and there were no differences between the groups. In the healthy control piglets, no change was seen in any variable during the 5-h study period.In the animals exposed to endotoxin alone (endotoxin group), MPAP was
increased more than twofold after 150 min of endotoxin infusion.
PaO2 was significantly reduced, to less than one-half the baseline value. HR increased and Qt decreased. There
were no significant differences between the values obtained 3, 4, and 5 h after the commencement of the endotoxin infusion (Table
1). There was no significant difference
in the increase in MPAP and decrease in PaO2 in
response to endotoxin infusion in the endotoxin, endotoxin + INO,
and endotoxin + INO + COX inhibitor groups before INO and the
COX inhibitor were administered.
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NO Inhalation and Discontinuation
In the endotoxin + INO group, inhalation of NO (30 ppm) after 3 h of endotoxin infusion resulted in a significant decrease in MPAP and a significant increase in PaO2. When, after 30 min, the NO inhalation was discontinued, MPAP increased rapidly (within 5 min) to a level that was 24% (P < 0.05) higher than before INO; thus a rebound response had occurred (Fig. 2A). PaO2 decreased rapidly to the pre-INO value (P > 0.05) but did not display a clear rebound phenomenon (Fig. 2C).
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When the NO inhalation was repeated 4 h after endotoxin infusion, the MPAP was significantly decreased, but the increase in PaO2 was small and no longer significant. Five minutes after discontinuation of NO inhalation, MPAP had again increased significantly to above the pre-INO level (P < 0.05) and PaO2 had fallen significantly to below the pre-INO level (P < 0.05). Thus distinct rebound hypoxemia had occurred (Fig. 2, B and D).
In the endotoxin + INO + COX inhibitor group, pretreatment with diclofenac tended to lower MPAP (P = 0.06) and to reduce oxygenation (P = 0.08). INO significantly decreased MPAP and increased PaO2. On discontinuation of INO, no rebound was observed in either MPAP or PaO2. Similarly, after a second INO challenge, no rebound response was recorded (Fig. 2).
INO had no significant effect in HR, system blood pressure, and
Qt (Table 2).
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Expression of COX-1 and COX-2
COX-1 expression in the lung tissue exposed to endotoxin alone (endotoxin group) did not differ compared with that in the healthy lung (Fig. 3A), but COX-2 expression in the endotoxin group was significantly higher than that in the healthy controls (Fig. 3B). The results indicate that COX-2 is upregulated by endotoxin exposure, but that COX-1 did not change.
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The expression of COX-1 was twice as high in the endotoxin + INO
group compared with that in the endotoxin group (P < 0.05; Fig. 4A), whereas the
expression of COX-2 was of the same magnitude in the endotoxin and
endotoxin + INO groups (Fig. 4B). This shows that COX-1
expression is upregulated by INO under endotoxemia.
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In the endotoxin + INO + COX inhibitor group, both COX-1 and COX-2 expression were significantly lower than in the endotoxin and endotoxin + INO groups (Fig. 4, A and B), indicating that both COX-1 and COX-2 expression are downregulated by diclofenac.
Concentration of Plasma TxB2
The plasma TxB2 concentration did not differ between the four groups at baseline and remained stable in the healthy controls (Fig. 5). Thirty minutes after the start of endotoxin infusion, this concentration had increased dramatically and then decreased to about four to five times the baseline level 2.5 h after the onset of endotoxin infusion, with no difference between the endotoxin-exposed groups. The plasma TxB2 then increased again throughout the study period.
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In the endotoxin + INO group, the plasma TxB2 concentration did not change during NO inhalation compared with that in the endotoxin control group (Fig. 5), but it was increased 5 min after INO withdrawal and peaked at 15 min after the withdrawal (P < 0.05). It then returned toward the same level as in the endotoxin controls. The pattern was similar when INO was withdrawn after the second trial (Fig. 5). In the endotoxin + INO + COX inhibitor group, the administration of diclofenac decreased the plasma TxB2 concentration, and this decrease reached significance 1 h later (i.e., 4 h after onset of the endotoxin infusion) compared with the value in the endotoxin and endotoxin + INO groups (Fig. 5).
Concentration of Plasma PGF2
between the four groups at baseline, and the plasma level remained stable throughout the study period in the healthy controls (Fig. 6). The plasma PGF2
concentration was increased five- to sixfold 30 min after the start of
endotoxin infusion with a further rise over the following 4.5 h of
the study. In the endotoxin + INO group, the plasma
PGF2 concentration did not change during NO inhalation
compared with that in the endotoxin control group (Fig. 6), but it was
increased 5 min after INO withdrawal and peaked at 15 min after the
withdrawal (P < 0.05). It then returned toward the
same level as in the endotoxin group. The pattern was similar when INO
was withdrawn after the second trial (Fig. 6).
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In the endotoxin + INO + COX inhibitor group, the plasma
PGF2 significantly decreased after administration of
diclofenac compared with the values in the other two groups that
received endotoxin (P < 0.05), and it remained at the
lower level throughout the study period (Fig. 6).
Concentration of Plasma 6-keto-PGF1
, a stable metabolite of PGI2,
was of the same magnitude in the four groups and remained stable in the
healthy controls (Fig. 7). This
concentration increased after 2 h of endotoxin infusion, and the
increase reached significance at 3 h in the endotoxin and
endotoxin + INO groups. In the endotoxin + INO + COX
inhibitor group, the plasma 6-keto-PGF1 level showed a
decrease after the administration of diclofenac. This decrease reached
significance at 4 h of endotoxin infusion compared with the values
in the endotoxin and endotoxin + INO groups (P < 0.05), and it remained at the lower level throughout the study period (Fig. 7).
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However, the increase of plasma 6-keto-PGF1 was
significantly lower than the increase in plasma TxB2 and
PGF2 in response to endotoxin infusion (Fig.
8).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, endotoxin infusion upregulated the
expression of the inducible COX and caused a marked increase in the
plasma concentrations of the prostanoids TxB2,
PGF2, and 6-keto-PGF1. In addition, an
upregulation of COX-1 expression by endotoxin and INO, and a further
increase in plasma TxB2 and PGF2 after INO
withdrawal during endotoxemia, were observed. The combination of INO
and a COX inhibitor eliminated the increase in prostanoids caused by
endotoxin and INO withdrawal and blocked the rebound response. These
results support our hypothesis that a short rebound response is related
to products synthesized via a COX-dependent pathway.
Endotoxin Model and INO
The initial phase of endotoxin exposure (0-2 h) seemed to be linked to the release of COX-synthesized products, in particular TxA2, a finding in accordance with results of others (16, 28). We also observed a time-dependent increase in the plasma level of TxB2 and PGF2 and a less pronounced increase in
6-keto-PGF1 (the metabolite of PGI2) on
endotoxin exposure. This may reflect a time- and dose-dependent
upregulation of COX-2 by endotoxin (4, 7, 25). Moreover,
the findings suggest that the increased PGF2,
TxB2, and PGI2 participated in the second
(2.5-5 h) prolonged increase in MPAP and decrease in
PaO2 and in the fall in systemic blood pressure.
NO inhalation did not alter the plasma prostanoid levels, but
TxB2 and PGF2 showed additional increases
after INO withdrawal, suggesting that they may play a role in the
rebound response on discontinuation of INO. It may also be hypothesized
that the increase in prostanoids contributed to the poorer response to
the second INO trial and seemingly to the stronger rebound reaction
after the second INO withdrawal, but this requires further study.
COX and Its Products
COX-1 is constitutively expressed in virtually all tissues and is responsible for the basal production of prostanoids for the maintenance of normal renal and gastric function, vascular hemostasis, and the autocrine response to circulating hormones (7). COX-2 is triggered by many factors, including endotoxin and cytokines, to release large amounts of prostanoids in inflammatory states (4, 7), but it is also constitutively expressed in some organs at a low level (7).We found that both COX-1 and COX-2 proteins are expressed in the healthy piglet lung and that endotoxin increases the COX-2 expression. This fits with previously demonstrated changes in mRNA (4, 18). Cross-talk between exogenous NO and COX has been observed, with exogenous NO activating COX-1, but the effects of NO on COX-2 are controversial (8, 24, 27). In the present study, INO during endotoxemia increased the COX-1 protein level compared with that in the healthy controls, but did not further increase the COX-2 protein level beyond that reached with endotoxin alone. As anticipated, strong coupling between the expression and activity of COX-2 has been shown (7), and we assume that this was also the case in the present study, although we did not measure COX activity.
Diclofenac is a nonselective, competitive, reversible inhibitor. It produces COX inhibition by competing with the substrate arachidonic acid for the active site of the enzyme (11, 15, 26). Our results show that it also decreases lung COX protein expression. Whether this decrease is caused by a downregulation of COX synthesis on a transcriptional or a posttranscriptional level, or by increased decomposition of COX protein, is not clear. We assume the decrease may be caused by increased breakdown of COX, after binding of its competitive inhibitor diclofenac.
Illogically, diclofenac also blocked the release of vasodilator
prostanoids, but our results and those of others (16)
indicate that the endotoxin-induced increases in the vasoconstrictors
TxA2 and PGF2 are much stronger than the
increase in the vasodilator PGI2 (Fig. 8). This may suggest
that, in this study, diclofenac mainly blocked the prostanoids that
acted as vasoconstrictors.
Rebound Phenomenon After INO Withdrawal
The rebound phenomenon after INO withdrawal has frequently been assumed to be due to reduction of endogenous NO production by a negative feedback effect of NO inhalation (2, 5, 9). However, in a previous study (5) on endotoxic piglets, there were indications that besides the decrease in endogenous NO production, increased activity of the vasoconstrictor ET-1 and possibly of other vasoconstrictor substances might be important in the rebound, in agreement with findings in a lamb model (21). The present study also proved that prostanoids play a role in the rebound reaction to INO withdrawal in our model.A clinical rebound phenomenon is reported after discontinuation of long-term NO inhalation (1, 10, 17). Whether the mechanisms of the clinical rebound are similar to those of the rebound reaction after a short period (30 min) of NO inhalation, as demonstrated here, were not tested in the present study but remains a possibility. Also, the study was performed in an endotoxin model, and whether a different lung damage model would yield the same results is not yet known.
The peak increase of plasma TxB2 and PGF2
levels after INO withdrawal appeared 10 min after the peak of the
rebound reaction in the present study. Whether this was an effect of
the time-dependent conversion of TxA2 to the metabolite
TxB2 or reflected involvement of other vasoactive
substances such as ET-1 is not clear. The conversion of
TxA2 to TxB2 takes only about a minute
(23). We therefore believe in the latter possibility and
assume that the increases in TxB2 and PGF2
after INO withdrawal are related to the increase in ET-1 during NO
inhalation (5).
ET-1 is an important releaser of TxA2 and
PGF2. When ET-1 binds to its receptors, it mediates
vasoconstriction by two pathways: 1) it changes
intracellular calcium; and 2) it stimulates secondary
release of the vasoconstrictors TxA2 and
PGF2 (21). This second pathway seems to be
a major mechanism in the pulmonary vasoconstriction induced by ET-1
injection (13). We have previously shown that the lung
tissue expression and plasma concentration of ET-1 increase during INO
in endotoxic piglets (5). INO seems to antagonize ET-1
binding to its receptor (12), and this antagonistic effect
might cease as soon as INO is discontinued. The increase in binding of
the available ET-1 to its receptor thus mimics an ET-1 injection.
Therefore, the rebound could be blocked both by a COX inhibitor and by
a nonselective ET-1 antagonist (21).
We conclude that the combination of INO with a COX inhibitor blocks the rebound reaction to acute INO withdrawal during endotoxemia. This may have important clinical implications.
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ACKNOWLEDGEMENTS |
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We thank Karin Fagerbrink and Agneta Roneus for assistance with the animal experiments.
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FOOTNOTES |
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This study was supported by Swedish Medical Research Council Grant 5315, the Swedish Heart-Lung Fund, the AB Gas Accumulator Medical Fund, the Laerdal Acute Medicine Fund, and Uppsala University.
Address for reprint requests and other correspondence: G. Hedenstierna, Dept. of Medical Sciences, Clinical Physiology, Univ. Hospital, SE-751 85 Uppsala, Sweden (E-mail: goran.hedenstierna{at}medsci.uu.se).
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.
10.1152/ajpheart.00535.2002
Received 27 June 2002; accepted in final form 21 August 2002.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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P < 0.05, difference
between the E + INO and E + INO + COX inhibitor
groups.
P < 0.05, difference between the E + INO + COX inhibitor and E + INO groups.
