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The plasma endothelin-1 (ET-1) level is elevated in patients with acute pulmonary thromboembolism (APE). Whether ET-1 is a pathogenic mediator or a simple marker of APE is not known. We investigated the role of ET-1 in hemodynamic dysfunction in APE through evaluating the effects of ETA receptor antagonist in an experimental APE model. We also examined ET-1 expression in embolized lungs. In a canine autologous blood clot pulmonary embolism model, ETA receptor antagonist ZD2574 (10 mg/kg, intravenous; ZD2574 group; n = 6) or vehicle (control group; n = 5) was administered. Hemodynamic and gas exchange parameters and plasma levels of ET-1 were serially measured. Prepro-ET-1 mRNA expression and the distribution of ET-1 peptide in lung tissues were also examined. With ZD2574 pulmonary arterial pressure and pulmonary vascular resistance significantly decreased, and were lower compared with the control group. The decrease in cardiac output was also less in the ZD2574 group. Plasma ET-1 levels increased after embolization. Prepro-ET-1 mRNA expression increased in embolized lungs and ET-1 peptide expression also increased in embolized lungs, particularly in the muscular pulmonary arteries, compared with normal lungs. These findings suggest that ET-1 partially contributes to hemodynamic derangements of APE, and that ETA receptor antagonists might constitute a useful therapeutic tool for APE.
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Keywords: embolism; endothelin; hemodynamics
Acute pulmonary thromboembolism (APE) causes a number of pathophysiologic derangements in cardiopulmonary function, and the abrupt increase in pulmonary vascular resistance that accompanies the massive pulmonary embolism is the principal cause of death in this disease (1). The degree of pulmonary vascular resistance is directly related to that of pulmonary vascular obstruction and that of neurohumorally mediated vasoconstriction (4, 5). Therefore, there could be two ways of managing the pulmonary arterial pressure overload in APE; one is to relieve the mechanical vascular obstruction and the other is to reverse the vasoconstriction mediated by neurohumoral factors. Options in the former, either thrombolytic therapy (3) or embolectomy (6), are invasive and dangerous and hence are limited to use in patients with severe hemodynamic derangements, and are usually delayed until a definitive diagnosis is made, during the initial critical period. Regarding the latter, numerous vasodilators have been tried, but have been found impractical because of their nonselective and deleterious effects on gas exchange and systemic hemodynamics (5, 7). So a new therapeutic option that is safe, effective, and readily available at bedside is needed.
Endothelin 1 (ET-1) is the most potent vasoconstrictor yet described (8), and has been implicated in the pathogenesis of pulmonary hypertension (9). Data suggest that abnormal ET-1 metabolism and subsequently elevated plasma ET-1 level occur in the acute phase of pulmonary embolism in humans (10). Furthermore, in the ex vivo isolated heart lung model with APE, ET-1 levels increased in the pulmonary effluent mediating coronary constriction and consequent cardiodepression (11). These findings suggest the possibility that ET-1 could be an important mediator in the hemodynamic derangements of APE. However, it is not known yet whether ET-1 is a "pathogenic mediator" or a "simple marker" of APE. Nor is it known whether the observed abnormality of ET-1 metabolism in APE relates to its defective pulmonary clearance or increased pulmonary production.
The purpose of this study was to evaluate the role of ET-1 in the pathogenesis of hemodynamic derangements of APE through investigating whether an ETA-receptor antagonist could ameliorate the hemodynamic derangements of APE in a canine model of autologous blood clot embolization. We also investigated whether the abnormal ET-1 metabolism in APE relates to its defective clearance or increased production in embolized lungs.
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Animal Preparation
Fifteen Korean mongrel dogs (mean weight of 17 kg with a range of 12 to 19 kg) were used. All procedures were approved by the animal care committee of Asan Medical Center (Seoul, Korea). The animals were intubated and mechanically ventilated with a servoventilator (Elema 900 B; Siemens Elema, Solna, Sweden). The inspired fraction of O2 was 21% and minute ventilation was adjusted to obtain an arterial PCO2 between 35 and 45 mm Hg. A thermodilution balloon-tipped pulmonary artery catheter (model 131H-7F; Baxter Edwards, Irvine, CA) was inserted through the left external jugular vein.
Autologous Blood Clot Embolization
Samples of venous blood (20 ml), collected before baseline measurements were performed, were allowed to clot in sampling bottles for
90 min and cut into 5-mm cubes, which were then infused via a large-bore cannula placed in the right atrium. Embolization was carried out
slowly for 5-10 min until the mean pulmonary arterial pressure (
)
reached 45 mm Hg.
Measurements of Hemodynamic and Gas Exchange Parameters
Pulmonary and systemic arterial pressure and cardiac output were determined. Pulmonary vascular resistance (RL) was calculated as
minus pulmonary capillary wedge pressure (Ppc,we) divided by cardiac output (
). Physiologic shunt (12) was calculated from the standard formula with capillary O2 content estimated from the calculated
alveolar O2 content and O2 saturations determined from the normogram of Rossing and Cain (13). Mixed expired gas was collected
through a collecting bottle and PCO2 was measured with an infrared
capnometer (Tonocap; Datex, Helsinki, Finland). The physiologic dead
space was calculated as the difference between arterial and mixed expired PCO2 divided by arterial PCO2 (14).
Experimental Protocol
Eleven dogs were assigned at random to two groups; the ZD2574 group (n = 6) received an intravenous infusion of ETA receptor antagonist ZD2574 (Zeneca Pharmaceuticals, Cheshire, England), dissolved in polyethylene glycol (10 mg/kg), and the control group (n = 5) received vehicle only. One hour after the start of clot infusion, we started infusing ETA receptor antagonist solution for 10 min. Hemodynamic and gas exchange parameters were measured before embolization (baseline), 1 h after embolization (PreRx), and every 30 min after administration of the ETA receptor antagonist or vehicle until 210 min after PreRx. To assess the independent effects of ZD2574, we measured hemodynamic and gas exchange parameters in four dogs without embolism, before and after ZD2574 infusion.
Measurements of Plasma ET-1
Arterial and mixed venous ET-1 levels were quantified by enzyme-linked immunosorbent assay (QuantiGlo QET00; R&D Systems, Minneapolis, MN). The monoclonal anti-ET-1 antibody used showed 27.4% cross-reactivity to ET-2, 7.8% cross-reactivity to ET-3, and less than 1% cross-reactivity to ET-1.
Northern Blot Analysis
For Northern blot analysis, RNA was extracted by the method of Chomczynski and Sacchi (15) from homogenized lung tissue from embolized (control group) and normal nonembolized dogs. A plasmid containing the ovine prepro-ET-1 cDNA probe (550 bp) was kindly provided by S. Abman (University of Colorado Health Sciences Center, Denver, CO).
Immunohistochemistry
Immunohistochemical staining was done with a monoclonal (mouse) anti-ET-1 antibody (MA3-005; Affinity BioReagents, Golden, CO), using a modification of the avidin-biotin-peroxidase method (16). Positive controls included lung tissues from patients with primary pulmonary hypertension (PPH) and negative controls were prepared with nonimmune serum instead of primary antiserum. Staining intensity was graded semiquantitatively from 0 to 3, with 0 representing the absence of any staining and 3 the maximal intensity, corresponding to the intensity of staining with factor VIII on parallel cuts. The grading was performed by two pathologists in a blinded manner.
Statistical Analysis
The group data are presented as means ± standard error of mean (SEM). Data were compared by analysis of variance for repeated measurements. Friedman and Wilcoxon signed rank sum tests for related samples were used to analyze the differences between pretreatment and treatment values at different time points. Adjustment was made for comparisons at multiple time points. Statistical significance was set at p < 0.05.
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Effects of Blood Clot Embolization on Hemodynamic and Gas Exchange Parameters
(See Tables 1 and 2.) There were no significant differences between the control and ZD2574 groups in weight, and basal
hemodynamic and gas exchange parameters. One hour after
embolization, , RL, PaCO2 , physiologic dead space, and
physiologic shunt increased and , PaCO2 , mixed venous oxygen tension (PvO2) and pH decreased significantly. Mean systemic arterial pressure (
) and Ppc,we were not affected by
embolization. There were no significant differences in all
these parameters between the ZD2574 and control groups.
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Effects of ZD2574 on Hemodynamic and Gas Exchange Alterations Induced by Embolization
(See Tables 1 and 2.) In the control group, after a stabilization
period of 1 h (PreRx), RL increased and decreased slowly and significantly with time during the experiment, while
did not change significantly. In the ZD2574 group, 30 min after treatment with ZD2574, and RL decreased significantly and were lower than those in the control group (Figure
1), and was significantly higher than that in the control
group (Figure 2). These differences continued until the end of
the experiment. In contrast, there were no significant differences between the two groups in , arterial oxygen tension,
physiologic shunt, and physiologic dead space.
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Effects of ZD2574 on Hemodynamic and Gas Exchange Parameters in Dogs without Embolism
To assess the independent effects of ZD2574, we measured
hemodynamic (, , RL, ) and gas exchange (PaO2 ,
physiologic shunt) parameters in four dogs without embolism,
before and every 30 min after ZD2574 infusion until 210 min
after ZD2574 infusion. There were no significant differences
in all these parameters before and after ZD2574 infusion.
Arterial and Venous Plasma ET-1 Levels
(See Table 3.) After embolization ET-1 levels were elevated in peripheral arterial and mixed venous plasma samples compared with those taken before embolization in the control group. The ratio of arterial to mixed venous plasma ET-1 concentration was not elevated significantly after embolization.
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Northern Blot Analysis
Prepro-ET-1 mRNA expression was significantly increased in embolized lungs (control group) compared with lungs from normal animals (Figure 3).
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Immunohistochemical Staining
Immunohistochemical analysis revealed mild ET-1-like immunoreactivity in normal lungs, particularly in the airways. In contrast, substantial staining was observed in sections from embolized lungs (control group), particularly in the muscular pulmonary arteries. The greatest degree of ET-1-like immunoreactivity was seen in the endothelium of muscular pulmonary arteries, while smooth muscle cells also showed moderate staining (Figure 4B). The mean level of ET-1-like immunostaining in the muscular pulmonary arteries was higher in embolized lungs (1.3 ± 0.21, p < 0.01) compared with that in normal lungs (0.5 ± 0.13) (Figure 5). Less pronounced increases in immunoreactivity were seen in the other vessels. No significant immunostaining was seen in the capillaries and alveolar epithelial cells, in both normal and embolized lungs (Figure 5).
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Pulmonary embolism can produce severe cardiopulmonary
dysfunction characterized by pulmonary arterial hypertension,
right ventricular failure, and hypoxemia. Although the major
noxious effect is attributed to direct mechanical obstruction of
pulmonary arteries, humoral mediators are released and are
believed to potentiate the pulmonary hypertension (4, 5). This
observation has been the justification for attempts at pharmacologic pulmonary vasodilation in these patients when right
ventricular failure occurs. The ideal vasodilator for such a purpose would decrease pulmonary arterial pressure with minimal systemic hypotension and no adverse effect on pulmonary
gas exchange. Many drugs including ketanserin have been
evaluated for their effectiveness as a pulmonary vasodilator.
However, none have gained widespread clinical use, either because of worsening hypoxemia (17) or significant systemic hypotension occurring frequently in this situation (20, 21). The limited therapeutic role of these vasodilators reflects their lack of selectivity for the pulmonary vasculature. In our study ET-1 mediated a part of the hemodynamic derangements in
APE, and the ETA receptor antagonist (ZD2574) improved
hemodynamic parameters (, RL, ) without causing either systemic hypotension or worsening hypoxemia.
ET-1 is a potent vaso- and bronchoconstricting peptide (22), and the lung is a major site for its synthesis, processing, and clearance. Under normal physiologic conditions, ET-1 levels in mixed venous blood entering the lung are normally higher than those in the systemic arterial blood leaving the lung. On the other hand, under pathologic conditions, such as primary or secondary pulmonary hypertension, the plasma ET-1 levels and the ratio of arterial to mixed venous (A/V) ET-1 levels were elevated (23). These findings have been interpreted as indicating a defective pulmonary clearance of the peptide and/or an increase in its pulmonary production due to the endothelial dysfunction. In the present study, the arterial and mixed venous plasma ET-1 levels increased significantly after embolization, and the A/V ratio also increased although the increase was not statistically significant. Through Northern blot analysis and immunohistochemical staining, we demonstrated that the elevated plasma ET-1 level and ET-1 A/V ratio were caused by increased ET-1 peptide production in embolized lung. The increased local levels of prepro-ET-1 mRNA and ET-1 peptide demonstrated in the embolized lung confirm that ET-1 may indeed play an important role in mediating the changes in APE at a cellular level.
In embolized lungs, upregulation of ET-1 peptide expression was most prominent in the muscular pulmonary arteries,
particularly in the endothelial cells. Several factors seem to be
involved in the stimulation of ET-1 expression in vascular endothelial cells in our study. After embolization, sharp reductions in circulating platelet numbers are observed (24). In our
study we also could observe significant reductions in circulating platelet numbers (control group, from 208 [±43] × 103 to
145 [±26] × 103/mm3; ZD2574 group, from 192 [±37] × 103 to
155 [±27] × 103/mm3). When a thromboembolus is lodged in
the pulmonary circulation, platelets may adhere, aggregate,
and be activated by thrombin in the embolus (25) and may in
turn secrete mediators including transforming growth factor 
(TGF-). By releasing TGF-, platelets stimulate ET-1 synthesis from bovine pulmonary artery endothelial cells (26).
Our experimental preparation of pulmonary embolism involves the use of fresh clot that has been divided into small segments. The large surface area and peripheral location of
these emboli may lead to more platelet activation than the
older and larger centrally located emboli that occur in humans. Caution must therefore be exercised in extrapolating
these results to patients. However, the degree of elevation of
plasma ET-1 levels after embolization in our study was comparable to that observed in humans (10). Hypoxemia, hemodynamic shear stress, and mechanical stretching due to elevated pulmonary arterial pressure could also stimulate rapid
ET-1 release from the vascular endothelial cells (22).
In our study ZD2574 decreased and RL, and increased
, compared with the control group. These favorable hemodynamic effects of ZD2574 could mainly depend on its activity
inhibiting pulmonary vasoconstriction induced by ET-1. But
other activities of ET-1 that could potentially be involved in
the hemodynamic derangements in APE warrant some consideration. Our data showed that ZD2574 attenuated the decrease in cardiac output. This effect of ZD2574 could be due
simply to reduction of acutely elevated right ventricular afterload by pulmonary vasodilation, which then permits increased left-sided filling and output. But other mechanisms should
also be considered because in several studies investigating the
effects of various vasodilators in experimental APE, cardiac
output did not improve, compared with the control group, despite significant decrease in Ppa and RL (27, 28). In a study of
a glass bead embolization model employing a heart-lung isolated ex vivo, it was revealed that ET-1 was increased in the
pulmonary effluent, mediating the coronary constriction and
consequent cardiodepression, and the ETA receptor antagonist could prevent the decrease in right ventricular contractility and coronary blood flow (11). These findings suggest that
ET-1 might be related not only to pulmonary vasoconstriction
but also to cardiodepression in APE. ET-1 may also cause pulmonary vasoconstriction by formation of secondary mediators. This idea is supported by the study showing that ET-1 activates the cyclooxygenase pathway, resulting in enhanced thromboxane A2 formation (29, 30). In vivo and in vitro, ET-1 causes coagulation in the microcirculation (31). In animal
models, ET-1 causes endothelial expression of von Willebrand
factor (32), a protein that leads to the vascular attachment of
platelets, an event that in turn enhances thrombus formation
(31). Increased ET-1 expression has been found in lung tissues
from patients with primary pulmonary hypertension (9), a
condition in which pulmonary vascular thrombosis is a common feature.
The pathogenic role of ET in the hemodynamic dysfunction of pulmonary embolism has also been studied in several experimental models other than thromboembolism. Nonselective antagonism of ET receptors attenuated the pulmonary hypertension and blunted the thromboxane A2 release caused by massive pulmonary air embolism in dogs (33). In isolated and ventilated rabbit lungs, pretreatment with ETA receptor antagonist significantly reduced the pulmonary arterial pressure reaction after air embolism (34). In a canine model of chronic embolic pulmonary hypertension induced by repeated embolization with ceramic beads, pulmonary vascular remodeling associated with elevated plasma ET-1 concentration and positive ET-1 immunoreactivity was attenuated by the ET receptor antagonist, bosentan (35).
In this study we used ETA receptor antagonist to test whether it could be a new therapeutic strategy in the management of APE, as well as to investigate the effect of ET-1 on pulmonary vasculature. The biological effects of ET-1 in mammals are mediated by at least two different receptors, ETA and ETB, both of which have been identified in the airway as well as in the pulmonary vasculature (22). Both types of receptor are located on the vascular smooth muscle cell and have constrictive properties. In contrast, a subpopulation of ETB receptors, located on the endothelium, mediates vasodilation through the release of nitric oxide and prostacyclin (22). So there is a possibility of conflicting actions if mixed A/B antagonists are used. In addition, in vitro, the endothelin-induced constriction of pulmonary arteries is mediated entirely by ETA receptors in dogs (36) and humans (37). ET-1 is also a bronchoconstrictor (22) and may thus have a role in the gas exchange alterations of APE, which was not the focus of our investigation. In humans, ET-1 induces bronchoconstriction through ETB receptors and approximately 80 to 85% of ET-1-binding sites in bronchial smooth muscle are ETB receptors (37). Accordingly it is possible that ZD2574 would have little chance to inhibit the effect of ET-1 on the airway. In our study ZD2574 did not cause any significant change in gas exchange parameters.
In the present study we have provided direct evidence of increased local production of ET-1 in embolized lung and showed that administration of the ETA receptor antagonist, ZD2574, improved the hemodynamic parameters in APE. These findings suggest that ET-1 partially contributes to the hemodynamic derangements of APE, and that ETA receptor antagonists might constitute a useful therapeutic tool for APE.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Sang-Do Lee, M.D., Ph.D., Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, College of Medicine, Ulsan University, 388-1 Poongnab-dong, Songpa-gu, Seoul, Korea. E-mail: sdlee{at}www.amc.seoul.kr
(Received in original form November 6, 2000 and accepted in revised form June 7, 2000).
Acknowledgments: The authors gratefully acknowledge the technical assistance of Kang Hyun Choe, Young Mi Kwon, and Youn Seong Kim.
Supported by grant 99-119 from Asan Life Science Institute. ZD2574 was provided by Zeneca Pharmaceuticals (Cheshire, England).
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References |
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