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1 Department of Clinical Physiology and 2 Department of Anesthesiology and Intensive Care, University Hospital, S-75185 Uppsala; and 3 Department of Urology and 4 Department of Physiology and Pharmacology, Karolinska Institute, S-17176 Stockholm, Sweden
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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On withdrawal of inhalation of nitric oxide (INO) administered after lung injury, pulmonary artery pressure (PAP) and arterial oxygen tension (PaO2) may deteriorate more than before INO (rebound response). In this study, we investigated the possible roles of endothelin (ET)-1 and nitric oxide (NO) synthase (NOS) activity in the short rebound reaction to short-term inhalation of NO. Twenty-six anesthetized mechanically ventilated piglets were given endotoxin infusion. Twelve animals then received INO (30 parts per million) for two 30-min periods. Nine controls were not given NO. Measurements were made of blood gases and hemodynamic parameters, lung tissue ET-1 expression and NOS activity, and plasma ET-1 concentration. INO decreased PAP and increased PaO2, but INO withdrawal caused a short rebound reaction with an increase in PAP. Lung tissue expression and plasma concentration of ET-1 increased during INO, and plasma ET-1 increased further after its withdrawal. Activity of constitutive NOS decreased during INO, whereas that of inducible NOS was unchanged. Upregulation of ET-1 and downregulation of NOS activity may have influenced the short rebound reaction to short-term INO.
endotoxin
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PULMONARY HYPERTENSION AND HYPOXEMIA are commonly observed in various forms of acute lung disease. Therapeutic inhalation of nitric oxide (INO) is considered to dilate pulmonary blood vessels selectively in ventilated areas, thereby reducing pulmonary vascular resistance and improving arterial oxygenation by redistribution of blood flow to ventilated areas of the lung. These changes occur within minutes after the initiation of nitric oxide (NO) therapy. However, on withdrawal of INO, both arterial oxygen tension (PaO2) and pulmonary artery pressure not only may be reversed to baseline (1, 19, 21, 26) but also may deteriorate to a greater extent than before the NO administration (8, 21, 20). Such a rebound response has been observed in patients with acute respiratory distress syndrome (ARDS) and severe hypoxemic respiratory failure and in infants that develop pulmonary hypertension after cardiac surgery (1, 8, 19-21, 26). Sudden withdrawal may lead to life-threatening hemodynamic instability, and deaths have been reported (8, 20). The mechanisms responsible for the rebound response are not fully understood. Knowledge of these mechanisms could lead to its prevention, which could have important implications for patients with pulmonary hypertensive disorders when interruption of NO inhalation is necessary or accidental. Such knowledge could also add to our understanding of the regulation of vascular tone.
It has been hypothesized that NO inhalation, through a negative feedback mechanism, reduces endogenous NO synthesis by downregulation of NO synthase (NOS) activity (1, 20, 21). This hypothesis has been tested in cell and tissue cultures and in animal experiments in vivo, but the results have been conflicting and inconclusive (2, 6, 15, 18, 25, 28, 32). Also, Horstman and co-workers (7) and Frank and co-workers (11) have found that 3 wk of inhaled NO did not decrease endogenous NO synthesis. Christou and co-workers (5) reported that INO did not decrease but increased the concentration of the circulating vasoconstrictor endothelin (ET)-1. We therefore hypothesized that a compensatory increase in the endogenous production of a vasoconstrictor, e.g., ET-1, may be a further mechanism underlying the rebound phenomenon in acute lung injury.
The purposes of the present study were 1) to mimic the rebound phenomenon found in humans by using an animal model in which a short-term rebound reaction occurs on discontinuation of short-term NO inhalation (here called "short rebound") and 2) to analyze the role of endogenous NO and ET-1 in the short rebound reaction.
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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. Twenty-six piglets of Swedish country breed, weighing 24-29 kg, were used in the study. Before they were transported from the farm, the piglets were sedated with a neuroleptic, azaperone (40 mg im; Stresnil, Janssen). Anesthesia was induced with 0.04 mg/kg im atropine, 6 mg/kg tiletamine-zolazepam (Zoletid, Virbac Laboratories), and 2.2 mg/kg xylazine chloride (Rompun, Bayer AG). After induction, a cannula was inserted in an ear vein and an opioid, fentanyl (5 µg/kg; Antigen Pharmaceuticals; Roscrea, Ireland), was injected. Muscle relaxation was achieved with 0.2 mg/kg pancuronium (Pavulon, Organon Technika; Göteborg, Sweden). Anesthesia was maintained with a continuous infusion of a hypnotic, clomethiazol (400 mg/h; Heminevrin, Astra; Södertälje, Sweden), and 2 mg/h pancuronium and 150 µg/h fentanyl. Repeated doses of fentanyl (200-500 µg iv) were given as necessary. The depth of anesthesia was considered to be adequate when skin incisions did not cause any changes in heart rate (HR) or blood pressure. Prewarmed (38°C) isotonic saline (500 ml/h) was given for hydration. The animals were placed in the supine position for the remainder of the study.A tracheotomy was performed after induction of anesthesia, and a cuffed tracheal tube (inner diameter, 6 mm) was inserted. Mechanical ventilation was provided in volume-controlled mode (Servo 900 C, Siemens-Elema; Lund, Sweden) at a respiratory frequency of 20 breaths/min, an inspiratory-to-expiratory ratio of 1:1, an end-inspiratory pause of 5%, and a positive end-expiratory pressure of 5 cmH2O. The inspired fraction of O2 was 0.5. 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.
Catheterizations for Blood Sampling and Pressure Measurements
A triple-lumen balloon-tipped catheter (Swan-Ganz 7-Fr) was introduced into the pulmonary artery via the right external jugular vein for blood sampling and pressure recordings. A large-bore catheter was inserted into the contralateral jugular vein for infusion purposes, with its tip in the superior vena cava. The right carotid artery was cannulated for blood sampling and recording of arterial blood pressure.The arterial, central venous, and pulmonary artery catheters were connected to the appropriate pressure transducers (Sorenson Transpac transducers, Abbott Critical Care Systems), and pressures were recorded on a Marquette 7010 monitor (Marquette Electronics). Mean arterial pressure, mean pulmonary artery pressure (MPAP), HR, central venous pressure, pulmonary capillary wedge pressure, and cardiac output were recorded. Airway pressures were registered from the ventilator. Vascular pressures were averaged over the whole respiratory cycle, and the midthorax was used as the zero reference level.
Cardiac output was measured by thermodilution; 10 ml of ice-cold isotonic saline was injected as a bolus and cardiac output was computed (cardiac output computer Marquette 7010, Marquette Electronics). At least three injections were given for each measurement, and the mean was calculated. The injections were evenly distributed over the respiratory cycle. The expired minute volume was recorded at each measurement.
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 were collected at the same time for biochemical analysis (see below).
NO Administration and Recording of NO in Respiratory Air
NO [1,000 parts per million (ppm) in N2] was added to a mixture of O2-N2 and connected to 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. The inspired fraction of O2 was checked after the addition of NO and kept stable at the pre-NO level.The NO concentration in exhaled air was measured intermittently during the experiment by chemiluminescence (chemiluminescence NO-NO2-NOx analyzer, model 42, Thermo Environmental Instruments, Franklin, MA).
Protocols
Thirty minutes after surgery, baseline measurements of hemodynamic parameters and blood samples were taken. Blood gas analyses were performed, and blood was collected for subsequent biochemical analysis. A septic model of acute lung injury was created by an intravenous infusion of endotoxin (lipopolysaccharide, Escherichia coli 0111:B4, Sigma; St. Louis, MO), which was given at a dose of 25 µg · kg
1 · h1 for 3 h and then maintained at 10 µg · kg1 · h1. The
hemodynamic and gas exchange responses were measured 30, 60, 120, and
180 min after the start of the endotoxin infusion. The piglets were
then allocated to one of the following three groups:
INO group (n = 12). After ~180 min of endotoxin infusion, inhalation of 30 ppm NO was started. After 15 min of INO and before its discontinuation after 30 min, further measurements of hemodynamic parameters and gas exchange were performed, and blood was sampled for biochemical analyses. INO was then withdrawn, and the measurements were repeated after 5, 10, 15, and 30 min to check for evidence of a short rebound reaction. Thereafter, INO was given for another 30 min and withdrawn again (from 240 to 270 min), and the same measurements were made over the next 30 min at the same time points as after the first INO challenge. This was done to see whether any short rebound reaction occurred and was stronger after NO inhalation after an additional hour of lung damage.
Lung tissue group (n = 5).
To measure the NOS activity and the ET-1 expression in vivo during
inhalation and after withdrawal of NO, lung tissue samples were
collected in vivo in five additional piglets. A median sternotomy was
performed, and the left pleura was opened. The incision was covered
with plastic film to prevent drying of the lung surface. The piglet was
ventilated for 1 h before baseline measurements were made. The
protocol was the same as in the INO piglet experiments except that NO
was administered for only one 30-min period and, in addition, a piece
of lung tissue was taken on four occasions (after 3 h of endotoxin
infusion, after 30 min of NO inhalation, and 15 and 30 min after NO
withdrawal). With a pair of forceps, a small part of the left middle
lobe was clamped, and a piece of lung tissue was cut off. For each new
sampling, another pair of forceps was used to clamp a piece of tissue
in the left middle lobe. The lung tissue sample was cut into blocks of
~0.5 × 0.5 × 0.3 cm, snap-frozen with liquid nitrogen,
and kept at 
80°C until NOS activity and Western blot measurements
were made.
Control group (n = 9). The control group received the same dose of endotoxin as the INO group. The setup of the mechanical ventilation was also the same, with O2 in N2, but no NO was inhaled. The control piglets were studied at baseline and at time points coinciding with the beginning and end of the two INO challenges in the INO group and also at the end of the experiment, 5 h after commencement of the endotoxin administration. This was done to check for the reaction to endotoxin per se.
Finally, all piglets were killed with an intracardiac injection of KCl. The total study time, including anesthesia, preparation, and baseline measurements before endotoxin infusion, was ~7 h. Two piglets died 10 to 15 min after INO withdrawal in the second trial of NO inhalation in the INO group.Plasma ET-1
Blood was collected in prechilled tubes containing EDTA (10 mM final concentration) and centrifuged (for 10 min at 4°C) to separate the plasma. Acid ethanol was added to precipitate the protein. The precipitate was finally analyzed for ET-1-like immune reactivity by radioimmunoassay using an antiserum (E1) raised against ET-1 in rabbits. The detection limit of the assay was 1.91 pM (17). The cross-reactivity of the E1 antiserum was as follows: ET-1, 100%; ET-2, 27%; ET-3, 8%; and Big ET-1, 0.14%. The level of the plasma ET-1 was expressed as picomoles per milliliter of plasma.ET-1 Expression Assessed by Western Blotting
The lung tissue blocks were rinsed with PBS at 4°C. The total protein of the lung tissue was extracted by homogenization (Ultra-Turrax, Jenke and Kunkel, IKA Labortechnik; Staufen, Germany) in five volumes 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 at80°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 sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electrophoretically transferred to a nitrocellulose membrane. The blot was blocked with 5%
BSA in Tris-buffered saline (TBS) overnight at 4°C and then incubated
with anti-ET-1 (1:5,000 dilution, Cambridge Research Biochemicals;
Cheshire, UK) in TBS containing 1% BSA overnight at 4°C.
After the blot was washed with TBS five times, it was incubated for
1 h with horseradish peroxidase-conjugated goat anti-rabbit IgG
(1:2,500 dilution, Vector Laboratories) for ET-1 detection. The blot
was then washed five times in TBS, after which the antigen-antibody
complex was detected on photographic film using enhanced
chemiluminescence reagent (Amersham; Arlington Heights, IL). According
to the manufacturer, the cross-reactivity of the ET-1 antiserum was as
follows: ET-1, 100%; ET-2, 9%; ET-3, 8%; and Big ET-1, 0.4%. All
the experiments were carried out three times, and the bands from each
experiment were analyzed using the NIH Image 1.6 C software program for
statistical analysis.
NOS Activity
NOS activity in lung tissue was measured by the conversion of L-[14C]arginine to L-[14C]citrulline. For the citrulline formation, lung tissues were homogenized in ice-cold homogenization buffer. Both calcium-dependent NOS (cNOS) and calcium-independent NOS (iNOS) were analyzed in the tissue extract (9). To determine the activity of cNOS, the analysis was carried out in the presence of NADPH, with EDTA and calcium as previously described. The method does not differentiate between the two isoforms of Ca2+-dependent NOS, neuronal NOS (nNOS) and endothelial NOS (eNOS). The activity of iNOS activity was measured similarly but without the presence of calcium (9). The level of citrulline was expressed as picomoles per gram of tissue (wet weight) per minute.Statistical Analysis
Means ± SD were calculated for all variables under all study conditions. Two-way ANOVA for repeated measurements was used for comparisons within and among groups. The least significant difference was used for post hoc tests. Differences were regarded as significant at a P level of <0.05. Simple regression analysis was used to analyze the correlation between changes in MPAP and PaO2 during INO and after INO withdrawal.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Endotoxin-Induced Lung Damage
The baseline values for the studied hemodynamic parameters were similar to those observed in healthy piglets in a previous experiment (12) (Table 1).
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After 3 h of endotoxin infusion, MPAP was increased more than twofold in both the control and INO groups. PaO2 was significantly reduced to one-half the baseline value. The HR was increased, and cardiac output was decreased. There were no significant differences between values obtained at 3 and 4 h after commencement of the endotoxin infusion in the INO group or between those obtained after 3, 4, and 5 h in the control group.
NO Inhalation and Discontinuation
After 3 h of endotoxin infusion, inhalation of 30 ppm NO for 30 min resulted in a 26% decrease in MPAP (P < 0.05; Fig. 1A) and a 59% increase in PaO2 (P < 0.05; Fig. 1C). When, after 30 min, the NO inhalation was discontinued, MPAP rapidly increased (within 5 min) to a level that was 23% (9 mmHg) higher than before the NO inhalation and significantly higher than in the control group (P < 0.05). Thus a short rebound reaction had occurred (Fig. 1A). PaO2 decreased rapidly after withdrawal of INO (P < 0.05), but no clear short rebound was seen (Fig. 1C). During the next 30 min after INO withdrawal, MPAP and PaO2 returned to their pre-NO inhalation levels.
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When the NO inhalation was repeated after 4 h of endotoxin infusion, the fall in MPAP and increase in PaO2 (26%) were less pronounced than during the test 1 h earlier, and the increase in PaO2 was no longer significant. Five minutes after discontinuation of the second 30 min of NO inhalation, MPAP had again increased significantly by 24% to a value above the pre-NO level (P < 0.05) and above that in the control group (P < 0.05; Fig. 1B). Meanwhile, PaO2 had decreased to a level 31% lower than the pre-INO value (P < 0.05). Thus a clear short rebound hypoxemic reaction had occurred (Fig. 1D).
There was an inverse relationship between the improvement in
PaO2 during NO inhalation and the magnitude of the
short rebound reaction of PaO2 on discontinuation of
NO (P < 0.05; Fig.
2B). Thus the weaker the
PaO2 response to inhaled NO, the greater the fall in
PaO2 when a short period of INO was discontinued. No
such relationship was observed for MPAP (P < 0.05;
Fig. 2A).
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In the control group, MPAP and PaO2 remained stable over the 2 h of the study period, corresponding to the INO challenges in the study group. Thus a comparison between the INO and control groups disclosed even more clearly the improvements in MPAP and PaO2 achieved by the two INO challenges and the short rebound reaction on discontinuation of NO (Fig. 1).
Plasma ET-1 Levels
Under baseline conditions, the plasma ET-1 concentration was of the same magnitude in the INO and control groups. After 3 h of endotoxin infusion, it had increased ~10-fold (P < 0.05) and showed no significant difference between the two groups (Fig. 3). In the control group, there was no further change in the plasma ET-1 level during the subsequent 2 h. In the INO group, plasma ET-1 increased further during and after the two INO trials, and the increase was significant in the second INO trial compared with the value before the INO challenges and the control group (P < 0.05; Fig. 3).
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Effect of INO on Expression of ET-1 in Lung Tissue (Lung Tissue Group)
The expression of ET-1 in the endotoxin-exposed lung increased more than threefold during NO inhalation compared with that before INO (P < 0.05). It then decreased after withdrawal of inhaled NO, and 30 min after cessation of INO, it had regained the pre-INO level (Fig. 4).
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NOS Activity (Lung Tissue Group)
NO inhalation downregulated the activity of cNOS, nNOS, and eNOS (Fig. 5A) but not of iNOS (Fig. 5B). Fifteen minutes after NO withdrawal, the iNOS activity was upregulated. At the same time, the cNOS activity had increased, and 30 min after discontinuation of INO, it had returned to the pre-INO level.
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NO in Expired Air
Expired NO was increased by 3 h of endotoxin infusion [from below 1 to ~4 parts per billion (ppb)] in both the INO and control groups (Fig. 6). There was no significant change in expired NO during the subsequent 2-h study period in the control group. In the INO group, expired NO was much higher during the first 5 min after NO discontinuation than before INO (80-100 compared with 4 ppb) and was still significantly higher (P < 0.05) than before NO therapy 10 min after cessation of INO. Thirty minutes after discontinuation of INO, expired NO had returned to the pre-INO level (Fig. 6).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Endotoxin Lung Damage
The endotoxin model triggers activation of a number of inflammatory markers (4) and has frequently been used as a model of septic acute lung injury. In this study, the exposure to endotoxin induced expression of iNOS, which plays a major role in NO production in inflammation, and the expired concentration of NO was also increased. We noted an improvement both in MPAP and arterial oxygenation on NO inhalation and a short rebound reaction on discontinuation of a short-term inhalation of NO. The endotoxin exposure also induced a pronounced increase in the plasma ET-1 concentration, and this was increased further by the INO challenges.ET-1 is a strong vasoconstrictor and a proinflammatory factor, acting via two subtypes of receptors (ETA and ETB) by direct receptor binding and/or by stimulating the release of thromboxane A2, another potent vasoconstrictor (22, 23). It has been reported that blockage of the ETA receptor abolishes the increase in MPAP that was noted 2 h after the start of endotoxin infusion (29) but not the early short-lasting increase 10-15 min after this start (31). This underscores the importance of ET-1 in the late phase of endotoxin-induced pulmonary hypertension.
INO and NOS Activity
NOS exists in different isoforms, including calcium-dependent eNOS and nNOS (the sum of the two is commonly called cNOS) and calcium-independent iNOS. eNOS is mainly distributed in the endothelial cells of vessels, and nNOS mainly occurs in nerve fibers near smooth muscle of airways and vessels. iNOS is mostly localized in the smooth muscles of blood vessels and airways and in epithelial and inflammatory cells. The activities of eNOS and nNOS could not be differentiated in this study. We assume that in lung tissue the detected cNOS activity can come from both eNOS and nNOS.In the present study, we found that exogenous NO only partly downregulated cNOS activity, conforming with the findings by Black and co-workers (2). It had no effect on iNOS activity, which is in line with the report by Griscavage and co-workers (15). Thus cNOS seems to be more sensitive than iNOS to the inhibitory action of NO. Also, 15 min after the withdrawal of inhaled NO, the iNOS activity was upregulated. This may be a compensatory mechanism by a system that is much more efficient in producing a large amount of NO than eNOS when inhaled NO is discontinued (27). Moreover, the expired NO concentration was much higher during the first 5 min after withdrawal of NO than at baseline and was still significantly increased 10 min after this withdrawal. This is most probably due to the presence of residual inhaled NO in the respiratory system. Although alveolar NO may not reflect the concentration of NO in the vascular smooth muscle cell, it suggests that more NO was available compared with baseline to keep the pulmonary vessels dilated at the time of the short rebound reaction.
INO and ET-1
Endogenous (3) but not exogenous NO (24) downregulates ET-1 synthesis. We found that exogenous NO did not decrease the plasma ET-1 concentration but that it upregulated ET-1 production in lung tissue, and, in the INO group, the plasma ET-1 level increased continuously during and after withdrawal of NO inhalation. Similar observations have been made in human neonates with primary pulmonary hypertension that received INO therapy (5). This increase may have been caused by INO, as supported by the absence of a further increase in plasma ET-1 in the control group during the same period, between 3 and 5 h of the study.It is reasonable to assume that exogenous NO interferes with the balance between ET-1 and endogenous NO and stimulates production of ET-1. The expression of ET-1 in lung tissue changed relatively quickly. ET-1 is converted from its proform, Big ET-1, by ET-converting enzyme (23). The ET-1 anti-serum used for this study is specific for ET-1 detection and has minimal cross-reaction with Big ET-1. We therefore conclude that the change in ET-1 expression could not have occurred at the transcriptional but at the posttranscriptional level. ET peptides are not stored within synthesizing cells but are produced constitutively and released to the extracellular medium at a steady rate (17). This makes it likely that ET peptides are mediators of slow physiological and pathological processes. However, a significant increase in the cellular expression of ET-1 mRNA and in the ET-1 concentration in culture media and bronchoalveolar lavage fluid has been seen shortly after stimulation (10, 13, 16, 30). This suggests that ET-1 may also mediate acute physiological effects, as suggested by our findings.
ET-1 expression was dramatically increased during NO inhalation. Its potential vasoconstrictive effect was obviously countered by the vasodilatory action of the inhaled NO. In addition, it has been shown that exogenous NO antagonizes ET-1 effects both at the level of direct ligand/receptor binding and by interference with the postreceptor pathway for calcium mobilization (14). This should also reduce the vasoconstrictive effect of ET-1. After withdrawal of INO, high concentrations of ET-1 were still circulating in the blood, coincident with the maximum short rebound reaction. Moreover, after NO withdrawal, the blockage of the signal transduction of the ETA receptor should have ceased. We therefore hypothesize that the increased concentration of the vasoconstrictor ET-1 and, possibly, increased availability of ETA receptor contributed to the short rebound reaction. The questions of whether prolonged NO inhalation would have enhanced this reaction and whether the mechanism of the clinical rebound phenomenon after several hours of INO is similar to that of the short rebound reaction were not tested in the present study, but they remain a possibility.
We also found that the weaker the response to INO, the greater the fall in PaO2 when INO was discontinued. A similar observation has been made in the patients receiving long-term INO treatment (8). Whether a poor or modest response to INO in an ARDS patient also signals the risk of a rebound response remains to be shown in clinical trials.
In conclusion, we consider that the short rebound reaction occurring on discontinuation of short-term NO inhalation is influenced not only by a downregulation of NOS activity but also, and possibly more importantly, by an increase in the amount of the vasoconstrictor ET-1 in the lung and circulating blood. However, clinical studies are needed before any extrapolation of the present findings to human conditions can be made.
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ACKNOWLEDGEMENTS |
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This study was supported by Swedish Medical Research Council Grants 5315 and 10354, the Swedish Heart-Lung Foundation, the AGA Medical Fund, the Laerdal Fund, and Uppsala University. E. F. Mondejar was the recipient of a grant from the Spanish Medical Research Council.
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FOOTNOTES |
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Present address of E. F. Mondejar: Servicio de Cuidados Críticos y Urgencias, Hospital Virgen de las Nieves, Granada, 18014 Spain.
Address for reprint requests and other correspondence: G. Hedenstierna, Dept. of Clinical Physiology, Univ. Hospital, S-75185 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.
Received 11 August 2000; accepted in final form 19 February 2001.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05 vs. control group.
; INO-1), and the second challenge
was after 4 h (
; INO-2). There was no difference
between the 3- and 4-h challenges. No correlation was seen for MPAP.
For PaO2, a significant correlation was found
according to the equation y = 35.9 + 0.45x; r = 0.73, P < 0.05.
P < 0.05 compared with value of pre-INO-2;
§P < 0.05 vs. control group.
