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1 Center for Anesthesiology Research and 2 Department of Thoracic and Cardiovascular Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio 44195
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested
the hypothesis that regulation of the pulmonary circulation by
endogenous endothelin (ET) during normoxia and hypoxia was altered in
conscious dogs 1 mo after left lung autotransplantation (LLA).
Sham-operated control and post-LLA dogs were chronically instrumented
to measure the left pulmonary vascular pressure-flow (LP-
) relationship. LP-
plots were generated on separate days during normoxia and hypoxia
(arterial PO2 ~50 Torr) in the
intact condition, after selective ETA-receptor inhibition (BQ-485), and after combined ETA+B-receptor inhibition
(bosentan). Although LLA resulted in a chronic increase in pulmonary
vascular resistance, the ET-receptor antagonists had no effect on the
LP- relationship during normoxia in either group.
The magnitude of hypoxic pulmonary vasoconstriction (HPV) was flow
dependent in both groups, and the HPV response was potentiated post-LLA
compared with control. ETA-receptor inhibition attenuated
the HPV response to the same extent in both groups.
ETA+B-receptor inhibition attenuated the HPV response to a
greater extent than did ETA-receptor inhibition alone, and
this effect was greater post-LLA compared with control. Plasma ET-1
concentration only increased during hypoxia in the LLA group. These
results indicate that ET does not regulate the baseline
LP- relationship in either group. Both
ETA- and ETB-receptor activation mediate a
component of HPV in conscious dogs, and the vasoconstrictor influence
of ETB-receptor activation is enhanced post-LLA.
pulmonary vascular pressure-flow relationship; endothelin-receptor antagonists; hypoxic pulmonary vasoconstriction
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ENDOTHELIN (ET)-1 is a 21-amino acid peptide released from vascular endothelial cells (53). ET has a potent vasoconstrictor effect mediated by several receptor subtypes (ETA and ETB receptors) (43, 46, 49). ET is known to be increased in some forms of chronic pulmonary hypertension (2, 3, 8). ET has also been implicated as a mediator of acute hypoxic pulmonary vasoconstriction (HPV) (5, 33, 48).
Our laboratory has been systematically investigating chronic changes in pulmonary vascular regulation that occur after left lung autotransplantation (LLA). This experimental model allows an assessment of the specific effects of the surgical transplantation procedure on the pulmonary circulation while avoiding the important but confounding effects of lung preservation techniques, immunosuppressive therapy, and tissue rejection. We have observed that LLA results in a chronic increase in pulmonary vascular resistance (26) and is characterized by abnormalities in neural (29), humoral (9), and local (30) mechanisms of pulmonary vasoregulation.
Because ET is known to be elevated in some forms of pulmonary hypertension, in the present study we tested the hypothesis that ET-receptor inhibition would attenuate the increase in pulmonary vascular resistance that occurs after LLA. Because of the putative role of ET in the HPV response, we also tested the hypothesis that ET-receptor inhibition would attenuate the magnitude of HPV in normal, conscious dogs. Finally, because the effects of lung transplantation on HPV have not been systematically examined, and because LLA results in endothelial dysfunction (30), we tested the hypothesis that the magnitude of HPV would be increased post-LLA.
Our studies utilized dogs that were chronically instrumented to measure
the left pulmonary vascular pressure-flow (LP-) relationship. This experimental model allows us to perform experiments with animals in the conscious state, which eliminates the effects of
anesthetics which are known to alter neural (4), humoral (32), and
local (25) mechanisms of pulmonary vascular regulation. Experiments
were performed ~4-5 wk after the surgical procedure; therefore,
the effects of acute surgical trauma were minimized. Finally, the use
of LP- plots avoids the problems inherent in the
interpretation of single-point calculations of pulmonary vascular resistance (14) and allows us to distinguish between active and passive
changes in the pulmonary circulation in response to the various interventions.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All surgical procedures and experimental protocols were approved by the Institutional Animal Care and Use Committee.
Surgical Procedures
Fourteen conditioned male mongrel dogs weighing 28 ± 1 kg were premedicated with 10 mg intramuscular morphine sulfate and anesthetized with 20 mg/kg intravenous pentobarbital sodium and 15 µg/kg fentanyl citrate. An endotracheal tube was inserted, and the lungs were mechanically ventilated. Anesthesia was maintained with ~1.2% end-tidal halothane. A left lateral thoracotomy was performed via the fifth intercostal space by using sterile surgical technique. The pericardium was incised ventral to the phrenic nerve. Heparin-filled Tygon catheters (1.02-mm ID; Norton, Akron, OH) were implanted in the descending thoracic aorta, main pulmonary artery, and left and right atria. The catheters were secured with purse-string sutures. A hydraulic occluder (18-mm ID; In Vivo Metric, Healdsburg, CA) was placed around the right main pulmonary artery, and an electromagnetic flow probe (10-mm ID, Zepeda, Seattle, WA) was implanted around the left main pulmonary artery.Seven dogs underwent LLA via sequential divisions and anastomoses of the left pulmonary veins, left mainstem bronchus, and left main pulmonary artery as previously described (26). The remaining seven dogs served as sham-operated controls. A wide circumhilar pericardial incision mobilized the left lung. After 3,000 U heparin were administered intravenously, the left pulmonary veins (inferior, middle, and superior) were individually dissected to their point of confluence with the left atrium. These veins were then cross clamped, divided, and anastomosed with a continuous stitch of 7-0 Prolene suture. The left mainstem bronchus was clamped distal to the carina, divided, and anastomosed by using a continuous stitch of 4-0 Prolene suture. The left main pulmonary artery was isolated, cross clamped, divided, and anastomosed with a continuous stitch of 6-0 Prolene suture. The left pulmonary artery cross-clamp time was ~15 min. Care was taken to avoid air emboli and luminal narrowing and to ensure good intimal apposition at the anastomotic sites.
The pericardial edges were loosely apposed, and the free ends of the catheters, hydraulic occluder, and flow probe were threaded through the chest wall and tunneled subcutaneously to a final position between the scapulae. A chest tube was placed in the left thorax before closure and was removed on the first postoperative day. Intramuscular morphine sulfate (10 mg) was administered postoperatively for pain, as required. Intravenous ampicillin (1 g), cephazolin (1 g), and gentamicin (80 mg) were administered intraoperatively and for 10 days postoperatively.
Experimental Measurements
Vascular pressures were measured by attaching the fluid-filled catheters to strain-gauge manometers (model P23 ID, Gould Statham, Eastlake, OH) and were referenced to atmospheric pressure with the transducers positioned at midchest at the level of the spine. Heart rate was calculated from the phasic aortic pressure trace. Left pulmonary blood flow (L) was measured by connecting
the flow probe to an electromagnetic flowmeter (model SWF-5RD, Zepeda). The flow probe was calibrated in vivo on a weekly basis by using the
thermal-dilution technique. A 7-Fr balloon-tipped catheter was inserted
percutaneously through an external jugular vein after topical lidocaine
anesthesia and was positioned 2-3 cm beyond the pulmonic valve.
The right pulmonary artery occluder was then inflated to direct total
pulmonary blood flow through the left pulmonary artery (and flow
probe). L was then measured by thermal dilution
(HEMOPRO2, Spectramed, Oxnard, CA) with multiple, 10-ml sterile injectants of 5% dextrose in water. Values for
L were referenced to body weight
(ml · min
1 · kg1).
Systemic arterial and mixed venous blood gases (pH,
PO2,
PCO2) were measured
with a Radiometer ABL-600 (Copenhagen, Denmark). Oxyhemoglobin
saturation (SO2) was measured with a
Radiometer Hemoximeter model OSM-3.
Experimental Protocols
All experiments were performed with each healthy unsedated conscious dog lying on its right side in a quiet laboratory environment. The seven LLA dogs were studied 30 ± 3 days after surgery. The seven sham-operated controls were studied 37 ± 3 days after surgery. Continuous LP- plots were used to assess the
pulmonary vascular effects of hypoxia and the ET antagonists.
LP- plots were constructed by continuously
measuring the pulmonary vascular pressure gradient [pulmonary
arterial pressure (PAP) 
left atrial pressure (LAP)] and
L during gradual (~1 min) inflation of the
hydraulic occluder implanted around the right pulmonary artery.
LP- plots are highly reproducible and have no
effect on systemic hemodynamics, blood gases, or the zonal condition of
the lung (28). Each dog was studied on 3 separate days in the intact
condition, after selective ETA-receptor block, and after
combined ETA+B-receptor block. The experiments were
performed in random order with regard to group and ET antagonists.
Because of technical failure (flow probes defective),
LP- plots were obtained in six dogs in each group.
Protocol 1: Effect of LLA on the magnitude of hypoxic pulmonary
vasoconstriction.
We tested the hypothesis that LLA would result in an increase in the
magnitude of HPV compared with normal conscious dogs. A baseline
LP- plot was obtained during normoxia in the
conscious state in six control dogs and six LLA dogs. A conical face
mask was then placed over each dog's snout. Room air was administered via the mask by using a semiclosed circulation system. After 15 min, a
normoxia LP- plot with face mask was obtained. The
delivered room air was then blended with gases from sources consisting
of 100% nitrogen, oxygen, or carbon dioxide. The gas flows were
titrated to the fraction of inspired oxygen tension (~11.2) that
resulted in a gradual decrease in systemic arterial
PO2 to ~50 Torr. After a new steady
state was reached (~30 min), a hypoxic LP- plot
was generated.
Protocol 2: Effect of selective ETA-receptor block on
the LP- relationship during normoxia and hypoxia
On a separate day, the procedures utilized in protocol 1 were
repeated in the same dogs after pretreatment with the selective ETA-receptor antagonist BQ-485
(perhydroazeptin-1-yl-L-leucyl-D-tryptophanyl-D-tryptophan: 10 µg · kg1 · min1
intravenous; a gift from Banyu Pharmaceuticals, Tsukuba, Japan). The
efficacy of ETA-receptor block was demonstrated by the
complete inhibition of the systemic pressor response to intravenous
ET-1 (400 ng/kg). LP- plots were generated during
normoxia, during normoxia after BQ-485, and during hypoxia. We tested
the hypotheses that ETA-receptor inhibition would cause a
downward shift in the baseline LP- relationship in
LLA dogs and that ETA-receptor block would attenuate the
magnitude of HPV in both control and LLA dogs.
Protocol 3: Effect of combined
ETA+B-receptor block on the
LP- relationship during normoxia and hypoxia.
On a separate day, the procedures utilized in protocol 1 were
repeated in the same dogs after pretreatment with the combined ETA+B-receptor antagonist bosentan {Ro 47-0203;
4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzene sulfonamide: 10 mg/kg bolus plus 10 mg · kg1 · h1
intravenous infusion; a gift from Hoffmann-LaRoche, Basel,
Switzerland}. The efficacy of ETA+B-receptor block
was demonstrated by the complete inhibition of the systemic pressor
response to intravenous ET-1 (400 ng/kg). LP- plots
were generated during normoxia, during normoxia after bosentan, and
during hypoxia. We tested the hypotheses that combined
ETA+B-receptor inhibition would inhibit the magnitude of
HPV to a greater extent than would ETA-receptor inhibition
alone and that this effect would be more pronounced in LLA dogs.
Measurement of Plasma ET-1 Concentration
Blood samples were simultaneously collected from the main pulmonary artery and the left atrium to measure plasma ET-1 concentration during normoxia and after 30 min of hypoxia in seven control and seven post-LLA dogs. The blood samples were placed in chilled tubes containing protease inhibitors. After centrifugation, the plasma was stored at20°C. After extraction through pretreated Sep-Pak
C18 columns (Waters Associates, Milford, MA), ET-1
concentration was measured in triplicate by radioimmunoassay (Peninsula
Laboratories, Belmont, CA).
Data Analysis
Phasic and mean vascular pressures and L were
displayed continuously on an eight-channel strip-chart recorder (model
2800, Gould, Eastlake, OH). Mean values for pressures and
L, measured at end expiration, were obtained with
passive electronic filters with a 2-s time constant. All vascular
pressures were referenced to atmospheric pressure before and after each
LP- plot. The analog pressure and
L signals were digitally converted and multiplexed (model PCM-8, Medical Systems, Greenvale, NY) and stored on videotape (videocassette recorder model AG-1260, Panasonic, Secaucus, NJ) for
later playback and analysis. The LP- relationship
was measured continuously over the empirically measured range of
L in each individual experiment. In all protocols,
the LP- relationship was linear by inspection over
the empirically measured range of L. Thus linear
regression analysis was used to calculate the slope and intercept for
PAP LAP (or PAP 0 if LAP 
0 mmHg) as a
function of L in each individual
experiment. The correlation coefficient for the LP-
relationship for each protocol averaged 
0.98. The composite
LP- plots in Figs. 1, 2, 4, and 6 were generated by
using the regression parameters from each individual continuously
measured LP- plot to calculate PAP LAP
at 10 ml · min1 · kg1 intervals of L over
the empirically measured range of
L. The minimum and maximum
values of L in each composite
LP- plot represent the average minimum and maximum
values of L for the dogs studied in that protocol.
Multivariate analysis of variance in the form of Hotelling's
T2 was used to assess the effects of mask, hypoxia,
BQ-485, bosentan, and LLA on the regression parameters obtained in each
individual experiment, compared with values measured at baseline (50). One-way and two-way analyses of variance were used to assess the effects of interventions on steady-state hemodynamics and blood gases.
Student's t-test for intragroup and intergroup comparisons was
used to compare the effects of BQ-485 and bosentan on the magnitude of
the HPV response and to assess changes in plasma ET-1 concentration
between normoxia and hypoxia. All values are presented as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of LLA on the Magnitude of HPV
As we have previously reported (26), LLA resulted in a marked leftward shift in the baseline LP- relationship compared with
conscious sham-operated, control dogs; i.e., LLA resulted in a chronic
increase in pulmonary vascular resistance (Fig.
1). The LP- relationships
during normoxia, normoxia with face mask, and hypoxia in control and
post-LLA dogs are summarized in Fig. 2.
Breathing room air through the face mask had no effect on the LP- relationship in either group, whereas breathing
the hypoxic gas mixture caused a leftward shift in the
LP- relationship in both control and LLA dogs.
The HPV response (i.e., the increase in PAP LAP from
normoxia to hypoxia at each common value of L) in
control and LLA dogs is compared in Fig. 3.
In both groups, the magnitude of HPV increased as L
increased. Moreover, at any given value of L, the
magnitude of HPV was increased post-LLA compared with control.
Steady-state hemodynamics and blood gases are summarized in
Tables 1 and
2, respectively. During normoxia, PAP was higher and
L was lower post-LLA compared with control. Hypoxia
increased PAP in both groups. Systemic arterial blood gases were
similar in control and LLA dogs during normoxia. Hypoxia increased
systemic arterial pH and decreased systemic arterial PCO2,
PO2, and
SO2, as well as mixed venous
PO2 and
SO2 to the same extent in both groups.
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Effects of ET-Receptor Block in Control Dogs
The selective ETA-receptor antagonist BQ-485 had no effect on the LP- relationship during normoxia (Fig.
4A). After ETA-receptor block, breathing the hypoxic gas mixture still caused a leftward shift
in the LP- relationship (Fig. 4A). However,
the magnitude of the HPV response was attenuated after
ETA-receptor block compared with the response measured in
the intact condition (Fig. 5). Combined ETA+B-receptor block with bosentan had no effect on
the LP- relationship during normoxia (Fig.
4B). Under these conditions, hypoxia still caused a shift in
the LP- relationship (Fig. 4B). However, the
magnitude of the HPV response was attenuated after combined
ETA+B-receptor block compared with the intact condition (Fig. 5). The magnitude of HPV was attenuated to a greater extent during combined ETA+B-receptor block compared with
selective ETA-receptor block (Fig. 5). Neither BQ-485 nor
bosentan had effects on steady-state hemodynamics or blood gases
(Tables 1 and 2).
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Effects of ET Receptor Block in Post-LLA Dogs
Neither selective ETA-receptor block (Fig. 6A) nor combined ETA+B-receptor block (Fig. 6B) had an effect on the LP- relationship during normoxia. Under these
conditions, hypoxia still caused a shift in the LP-
relationship (Fig. 6). The magnitude of HPV was attenuated by selective
ETA-receptor block and was reduced to an even greater
extent by combined ETA+B-receptor block (Fig.
7). BQ-485 decreased the HPV response to a
similar extent in control and post-LLA dogs, whereas bosentan
attenuated the HPV response to a greater extent in the LLA group (Fig.
8). Neither ET-receptor antagonist had an
effect on steady-state hemodynamics or blood gases (Tables 1 and 2).
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Plasma ET-1 Concentrations During Normoxia and Hypoxia in Control and LLA Dogs
Pulmonary arterial and left atrial plasma ET-1 concentrations were similar during normoxia in control and LLA dogs (Fig. 9). Hypoxia induced a small increase in the left atrial plasma ET-1 concentration in LLA dogs but not in control dogs (Fig. 9).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The overall goal of this study was to investigate the role of endogenous ET in regulation of the pulmonary circulation after LLA. Our main findings are the following: 1) ET does not mediate the chronic increase in pulmonary vascular resistance post-LLA, 2) the magnitude of HPV is enhanced post-LLA, 3) both ETA- and ETB-receptor activation are involved in the HPV response in control and LLA dogs, and 4) the vasoconstrictor role of ETB-receptor activation during HPV is potentiated post-LLA.
As our laboratory has previously reported (26, 29-31), LLA
resulted in a chronic increase in pulmonary vascular
resistance. Sympathetic 
1-adrenoreceptor
activation mediates a portion of this effect, because inhibition of
1-adrenoreceptors partially reverses the shift in the
LP- relationship post-LLA (29). Angiotensin
II-receptor activation also mediates a component of the increase in
pulmonary vascular resistance post-LLA (9). We postulated that
endogenous ET may also be involved in the chronic increase in pulmonary
vascular resistance post-LLA. The rationale for this hypothesis is that
ET has been implicated in experimental (5, 15, 24, 47) and human (2, 3,
8) pulmonary hypertension. Moreover, LLA is characterized by profound
abnormalities in endothelial function (11, 37, 54). However, neither of the ET antagonists had an effect on the baseline LP-
relationship during normoxia. Thus endogenous ET does not mediate the
active increase in pulmonary vascular resistance post-LLA. However, our experimental design does not rule out the possibility that ET may exert
chronic effects on the pulmonary circulation (e.g., structural changes)
post-LLA.
The vascular actions of ET are mediated by at least two receptor subtypes, ETA and ETB receptors. Classically, it was thought that activation of ETA receptors on vascular smooth muscle caused vasoconstriction, whereas activation of ETB receptors on endothelial cells caused vasodilation via the release of endothelium-derived relaxing factors. However, recent evidence suggests that ETB-receptor activation can also result in vasoconstriction in human blood vessels (39), including pulmonary artery (21). At present it is uncertain whether different subtypes of ETB receptors are present on endothelial and vascular smooth muscle cells (7). One possible limitation of our study is that we did not utilize a selective ETB-receptor antagonist. We assumed that differences between the effects of BQ-485 and bosentan are due to the net effect of inhibiting ETB receptors.
HPV is a compensatory mechanism whereby a decrease in alveolar PO2 results in constriction of adjacent pulmonary arterioles, which improves gas exchange by diverting pulmonary blood flow away from hypoxic regions to better ventilated regions of the lung. The mechanism responsible for HPV is intrinsic to the lung, because HPV has been demonstrated on numerous occasions in isolated lung preparations. There are conflicting reports in the literature concerning the role of ET in the HPV response. Evidence to support a role for ET has been reported in rats (5, 6, 15, 33), lambs (48), pigs (12, 16, 17), and dogs (51). Conversely, ET was not found to play a role in the HPV response in rats (13, 45), lambs (52), and dogs (10). Possible confounding factors that could be responsible for these conflicting results include the use of anesthetics, acute surgical trauma, artificial perfusion, and single-point calculations of pulmonary vascular resistance. Our experimental model avoids these confounding factors. Our results suggest that both ETA- and ETB-receptor activation mediate components of the HPV response. Both ET antagonists attenuated the HPV response. Moreover, the effects of combined ETA+B-receptor block were greater than those of selective ETA-receptor block.
The LLA procedure results in surgical denervation of the lung. We did not anticipate that denervation per se would alter the HPV response post-LLA, because we have previously demonstrated that the autonomic nervous system does not mediate or modulate the HPV response in conscious dogs (20). It is known in a qualitative sense that the HPV response persists in the human transplanted lung (23, 35). We observed that the HPV response was potentiated post-LLA. Although the precise mechanism that mediates HPV remains to be elucidated, it is well established that several endogenous vasodilator mechanisms (e.g., nitric oxide, prostacyclin, ATP-sensitive K channel activation) act to modulate the HPV response (18, 19, 27). Pulmonary vasodilation mediated by nitric oxide (37) and ATP-sensitive K channel activation (38) are attenuated post-LLA. Thus the potentiated HPV response post-LLA could be due to a reduction in the influence of these vasodilator pathways. In addition, in the present study we observed that the inhibitory effect of ETA-receptor block was similar in control and LLA dogs, whereas the effect of combined ETA+B-receptor block was greater post-LLA compared with control. One possible explanation for these results is a shift in the relative contribution of endothelial and vascular smooth muscle ETB receptors post-LLA. For example, If the vasodilator influence of endothelial ETB-receptor activation is diminished post-LLA, this would result in a potentiated HPV response mediated by vascular smooth muscle ETB-receptor activation.
There is a relative paucity of information concerning the role of ET in the setting of lung transplantation. Combined ETA+B-receptor block has been shown to ameliorate ischemia-reperfusion injury in canine lung allografts (40). Plasma ET concentrations are elevated after experimental (40, 41) and human (42) lung transplantation, although values return to baseline concentrations within 1 wk of the transplantation procedure. ET is also increased in the bronchoalveolar lavage fluid of patients with lung allografts (1, 36). It has been postulated that ET may be involved in chronic rejection and the development of obliterative bronchiolitis (22, 34, 44). We did not observe an increase in plasma ET concentration during normoxia after LLA, perhaps because measurements were made 1 mo after the LLA procedure. More surprisingly, we did not observe an increase in plasma ET in response to hypoxia in the control group and only observed a small increase in the LLA group. This result appears to be inconsistent with the marked effects of the ET antagonists on the HPV response. We can only speculate that plasma concentrations of ET do not accurately reflect the local tissue concentration.
It is important to note that the magnitude of HPV was directly proportional to the level of pulmonary blood flow in both control and post-LLA dogs (Figs. 3, 5, and 7). The flow-dependent nature of HPV must be taken into account when investigating the effects of physiological or pharmacological interventions on the HPV response. This factor may account for some of the conflicting reports in the literature concerning the role of ET in the HPV response.
In summary, ET does not mediate the chronic increase in pulmonary vascular resistance post-LLA. Both ETA- and ETB-receptor activation mediate components of the HPV response. The vasoconstrictor role of ETB-receptor activation during HPV appears to be potentiated post-LLA.
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ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge the technical support of Steve Schomisch, Pantelis Konstantinopoulos, and Mike Trentanelli. The authors also thank Cassandra Talerico for outstanding work in preparing the manuscript. They also thank Banyu Pharmaceuticals and Hoffmann-La Roche for their kind gifts of BQ-485 and bosentan, respectively.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grants HL-40361 and HL-38291. S. Doi was also supported by Dr. Jun-ichi Yata (Dept. of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan).
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: P. A. Murray, Center for Anesthesiology Research, FF40, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195 (E-mail: murrayp{at}ccf.org).
Received 16 February 1999; accepted in final form 14 September 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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P < 0.01) by bosentan. Values
are means ± SE.
P < 0.01) by bosentan. Values are means ± SE.
