0
Original Research: PULMONARY HYPERTENSION |

Bosentan Decreases Pulmonary Vascular Resistance and Improves Exercise Capacity in Acute Hypoxia FREE TO VIEW

Vitalie Faoro, MSc, PhD; Saskia Boldingh, MSc; Mickael Moreels, MD; Sarah Martinez, MSc; Michel Lamotte, MSc; Philippe Unger, MD, PhD; Serge Brimioulle, MD, PhD; Sandrine Huez, MD, PhD; Robert Naeije, MD, PhD
Author and Funding Information

*From the Department of Physiology (Drs. Faoro and Naeije, and Ms. Martinez), Faculty of Medicine, Free University of Brussels, Belgium; VU University Medical Center (Ms. Boldingh), Amsterdam, the Netherlands; and the Departments of Cardiology (Drs. Moreels, Unger, and Huez, and Mr. Lamotte), and Intensive Care (Dr. Brimioulle), Erasme University Hospital, Brussels, Belgium.

Correspondence to: Robert Naeije, MD, PhD, Department of Physiology, Erasme Campus CP 604, 808 Lennik Rd, B-1070 Brussels, Belgium; e-mail: rnaeije@ulb.ac.be


Supported by the Foundation of Cardiac Surgery and by the Fonds de la Recherche Scientifique Médicale (grant No. 3.4551.05), Belgium. Dr. Huez was a fellow of the Fonds National de la Recherche Scientifique, Brussels, Belgium.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;135(5):1215-1222. doi:10.1378/chest.08-2222
Text Size: A A A
Published online

Background:  Altitude exposure is associated with mild pulmonary hypertension and decreased exercise capacity. We tested the hypothesis that pulmonary vascular resistance (PVR) contributes to decreased exercise capacity in hypoxic healthy subjects.

Methods:  An incremental cycle ergometer cardiopulmonary exercise test and echocardiographic estimation of pulmonary artery pressure (Ppa) and cardiac output to calculate total PVR were performed in 11 healthy volunteers in normoxia and after 1 h of hypoxic breathing (12% O2). The measurements were performed in a random order at 1-week intervals after the receiving either a placebo or bosentan, following a double-blind randomized crossover design. Bosentan was administered twice a day for 3 days, 62.5 mg on the first day and 125 mg on the next 2 days.

Results:  Hypoxic breathing decreased the mean (± SE) pulse oximetric saturation (Spo2) from 99 ± 1% to 3 ± 1% and increased the mean PVR from 5.6 ± 0.3 to 7.2 ± 0.5 mm Hg/L/min/m2, together with a decrease in mean maximum O2 uptake (V̇o2max) from 47 ± 2 to 35 ± 2 mL/kg/min. Bosentan had no effect on normoxic measurements and did not affect hypoxic Spo2, but decreased PVR to 5.6 ± 0.3 mm Hg/L/min/m2 (p < 0.01) and increased V̇o2max to 39 ± 2 mL/kg/min (p < 0.01) in hypoxia. Bosentan therapy, on average, restored 30% of the hypoxia-induced decrease in V̇o2max. Bosentan-induced changes in Ppa and V̇o2max were correlated (p = 0.01).

Conclusions:  We conclude that hypoxic pulmonary hypertension partially limits exercise capacity in healthy subjects, and that bosentan therapy can prevent it.

Figures in this Article

High-altitude exposure has long been known to decrease aerobic exercise capacity. This is explained by a decrease in O2 delivery to the tissues, due to decreases in both arterial O2 content and in maximum cardiac output (Q).1 Acclimatization is associated with a restoration of arterial O2 content due to hyperventilation and increased hemoglobin content. However, exercise capacity remains decreased, which is at least partly related to a decrease in maximum Q.1,2 The mechanisms of decreased maximum Q at high altitudes are not entirely clear.3 A recently raised possibility is that of a limitation in right ventricular flow output by hypoxic pulmonary vasoconstriction. An improvement in exercise capacity together with a decrease in pulmonary artery pressure (Ppa) was indeed reported after the intake of sildenafil in hypoxic healthy volunteers.4 However, these effects did not appear to be sustained and could be ascribed at least in part to an associated improvement in arterial oxygenation.5

We therefore investigated the effects of the endothelin (ET) A and ETB receptor blocker bosentan on the pulmonary circulation and on exercise capacity in hypoxic healthy volunteers. Bosentan is an efficient therapy of pulmonary arterial hypertension6 and decreases Ppa levels in healthy subjects after a rapid ascent to high altitude.7 The drug is without effects on systemic BP, ventilation, or arterial oxygenation in acute hypoxic conditions.7,8 Accordingly, the hypothesis tested in the present study was that a specific decrease in pulmonary vascular resistance (PVR) by the intake of bosentan would improve aerobic exercise capacity in healthy acutely hypoxic subjects.

Subjects

Eleven healthy volunteers (2 women and 9 men; age range, 20 to 45 years; mean age, 29 years; mean [± SD] height, 178 ± 10 cm; mean weight, 70 ± 11 kg) gave written informed consent to the study, which was approved by the Ethics Committee of the Erasme University Hospital. All the subjects were healthy and active, with an unremarkable medical history, and normal clinical examination and ECG findings. They had been prescreened to ensure good quality echocardiographic signals.

Experimental Design

Each subject underwent an echocardiographic examination in a semirecumbent position, at rest and at a moderated level of exercise to increase Q, so as to define PVR by the measurement of Ppa at several levels of flow, and an incremental maximum cycle ergometer cardiopulmonary exercise test (CPET) at a fraction of inspired oxygen (Fio2) of 0.21 (while breathing room air) or at an Fio2 of 0.12 (while breathing from a premixed tank of O2 in nitrogen). The subjects were equipped with tightly fitted facial masks in all experimental conditions. The facial mask was open to the atmosphere in normoxia and connected to the low O2 tank with an interposed Douglas bag in hypoxia. The echocardiographic examinations and CPET were performed consecutively after the intake of bosentan, 62.5 mg bid followed by 125 mg bid for 2 days, or a placebo according to a double-blind, randomized, placebo-controlled crossover design. The sequence of Fio2 0.21 and 0.12 measurements was also randomized. The echocardiographic measurements were started 1 h after the subjects had been equipped with a face mask and were breathing either room air or the hypoxic gas mixture. The hypoxic breathing was not interrupted between the echocardiographic and CPET measurements. The average duration of the echocardiographic measurements was 20 min. The average duration of the CPET was 10 to 12 min. Therefore, the total duration of hypoxic exposure was approximately 90 min.

The dose of bosentan had been decided on the basis of the upper range of doses recommended for the treatment of pulmonary hypertension,6 and it had previously been shown7 to decrease hypoxic pulmonary hypertension in healthy volunteers. The Fio2 of 0.12 was selected as being associated with a safe and near maximal hypoxic pulmonary vasoconstriction.4,5,9,10

Thus, every subject underwent a total of four sequences of echocardiographic examinations and CPET. Each of these sequences was performed at least 7 days apart, with the subjects in a resting state with stable systemic arterial pressure (Psa) and heart rate (HR). The subjects were requested to drink 1.5 L of water within the hour preceding the echocardiographic examination to optimize the Doppler signals. The echocardiographic examinations and CPET were performed under constant clinical supervision and monitoring of the ECG and O2 saturation, with measurements of Psa made at regular intervals.

Clinical Measurements

Psa was measured by sphygmomanometry, with mean pressure calculated as diastolic pressure + one third pulse pressure. A three-lead ECG was used to measure HR. Pulse oximetric saturation (Spo2) was measured by an earlobe pulse oximeter (Pulsox-3i; Konica Minolta Sensing; Osaka, Japan). The device was tested and calibrated following the manufacturer's recommendations. Particular attention was paid to the quality of the signal, especially during exercise, because it is known that the accuracy and precision of pulse oximetry at exercise may be decreased by local perfusion.11

Echocardiography

Echocardiography was performed using a portable ultrasound system equipped with a 2.5-MHz probe (Cypress; Acuson/Siemens; Erlangen, Germany). Recordings were stored on optical disks and analyzed by two independent blinded cardiologists experienced in echocardiography. Q was estimated from left ventricular outflow tract cross-sectional area and pulsed Doppler velocity-time integral measurements.12 Systolic Ppa (sPpa) was estimated from a transtricuspid gradient calculated from the maximum velocity of continuous Doppler tricuspid regurgitation, with 5 mm Hg assigned to right atrial pressure.10,13 Mean Ppa (mPpa) was calculated as 0.6 × sPpa + 2.14 PVR was calculated as mPpa/Q.

Exercise echocardiography was performed on a supine ergometer (model 900 EL; Ergoline; Bitz, Germany), as previously described.10 The exercise table was tilted laterally by 20 to 30 degrees to the left. After obtaining Doppler echocardiographic images at rest, exercise was started at an initial workload of 20 W. Workload was increased by 20 W every 2 min. Three to five pressure-flow coordinates were recorded in every subject, at levels of exercise below the anaerobic threshold (AT), and therefore without excessive increase in ventilation and/or discomfort to allow for optimal quality echocardiographic measurements. Thus, the achieved workload was on average 80 W, and the exercise echocardiography lasted on average of 8 min.

Cycle Ergometer CPET

The CPET was performed in an erect position on an electronically braked cycle ergometer (Monark; Ergomedic 818 E; Vansbro, Sweden) with breath-by-breath measurements, through a tightly fitted facial mask, of minute ventilation (V̇e), oxygen uptake (V̇o2), and carbon dioxide output (V̇co2) using a cardiopulmonary exercise system (Oxycon Mobile; Jaeger; Hoechberg, Germany). The metabolic card was adapted for hypoxic measurements and calibrations performed accordingly. As with the echocardiographic measurements, a Douglas bag was interposed between the hypoxic gas mixture tank and the facial mask during hypoxic exercise. After a 3-min warm-up at 0 W, the work rate was increased at each step by 15 to 30 W according to previous CPET and predicted decrease by approximately 35% in hypoxia such as for the test to last for 10 to 12 min.15 Maximum V̇o2 (V̇o2max) was defined as the V̇o2 measured during the last 20 s of peak exercise. The respiratory exchange ratio (RER) was calculated as V̇co2/V̇o2, and O2 pulse as V̇o2/HR. The ventilatory equivalents for CO2 (V̇e/V̇co2) were calculated by dividing V̇e by V̇co2. The AT was estimated by the V-slope method.15

Statistical Analysis

Results are presented as the mean ± SE. The multipoint sPpa/Q coordinates obtained by exercise were pooled using a normalization procedure allowing for mild nonlinearities and state-dependent variability.16 The statistical analysis consisted of a two-way analysis of variance. When the F ratio of the analysis of variance reached a p < 0.05 critical value, paired or unpaired modified Student t tests were applied as indicated to compare specific situations.17

Exposure to hypoxia was well tolerated, excepted for a transient and mild headache in some subjects. One of the subjects complained of fatigue, facial edema, and severe headache during the entire period of bosentan intake. No other side effects of bosentan were recorded. Baseline routine echocardiographic measurements remained unaltered throughout the study.

Effects of Hypoxia

Hypoxia decreased Spo2, and increased HR, Q, sPpa, and PVR, while Psa remained unchanged (Table 1). mPpa-Q plots were linear, with a correlation coefficient > 0.9 in all of the subjects. Hypoxia shifted mPpa-Q plots to higher pressures (Fig 1).

Table Graphic Jump Location
Table 1 Effects of Bosentan on Hemodynamics and Oxygen Saturation in Normoxia and in Hypoxia in Normal Subjects at Rest*

*Values are given as the mean ± SD. Hypoxia = Fio2 0.12.

†p < 0.05 vs low altitude.

‡p < 0.001 vs low altitude.

§p < 0.01 vs low altitude.

‖p < 0.01 vs placebo in high altitude.

Figure Jump LinkFigure 1 Pooled mPpa vs cardiac index relationships in 11 healthy subjects before (■) and during hypoxic breathing (♦). The calculated regressions are represented by full and dotted lines, respectively. Hypoxia shifted pressure-flow relationships to higher pressures, indicating hypoxic pulmonary vasoconstriction.Grahic Jump Location

Hypoxia decreased maximum workload, V̇o2max, maximum V̇e (V̇emax), maximum HR (HRmax), O2 pulse, V̇o2, and workload at the AT, and Spo2, while V̇e/V̇co2 at the AT was increased, and the maximum RER achieved was higher than that in normoxia (Table 2).

Table Graphic Jump Location
Table 2 Effects of Bosentan on Cardiopulmonary Exercise Variables in Normoxia and in Hypoxia in Healthy Subjects*

*Values are given as the mean ± SD. Workload max = maximum workload; RERmax = maximum RER. See Table 1 for abbreviation not used in the text.

†p < 0.001 vs low altitude.

‡p < 0.05 vs placebo in acute hypoxia.

§p < 0.01 vs placebo in acute hypoxia.

‖p < 0.05 vs low altitude.

¶p < 0.01 vs low altitude.

Effects of Bosentan

Bosentan in normoxia had no effect on hemodynamic or CPET variables, and it did not affect resting or exercise Spo2 (Tables 1, 2). Bosentan had no effect on mPpa-Q plots in normoxia (Fig 2).

Figure Jump LinkFigure 2 Pooled mPpa vs cardiac index relationships in 11 healthy subjects before (■) and after bosentan intake (□) in normoxia. The calculated regressions are represented by full and stippled lines, respectively. Bosentan had no effect on pressure-flow relationships, indicating an absence of effect on resting pulmonary vascular tone.Grahic Jump Location

Bosentan administration with the subject in hypoxia decreased sPpa and PVR without any effect on HR, Spo2, Psa, and Q (Table 1), shifted mPpa-Q plots to lower pressures (Fig 3), increased V̇o2max and maximum workload despite a lesser increase in maximum RER compared to placebo, and increased O2 pulse without an effect on V̇emax, V̇e/V̇co2, HRmax, and V̇o2, and workload at the AT (Table 2). Bosentan administration attenuated the reduction in V̇o2max observed during acute hypoxia by approximately a third. Bosentan administration during hypoxia increased V̇o2max and decreased sPpa in all the subjects, except in the one subject who had presented with side effects (Fig 4, 5).

Figure Jump LinkFigure 3 Pooled mPpa vs cardiac index relationships in 11 healthy subjects before (♦) and after bosentan intake (◇) in hypoxia. The calculated regressions are represented by full and dotted lines, respectively. Despite individual variability, bosentan shifted pressure-flow relationships to lower pressures, indicating the inhibition of hypoxic pulmonary vasoconstriction.Grahic Jump Location
Figure Jump LinkFigure 4 Individual changes in sPpa induced by the intake of bosentan in hypoxia. All the subjects except one with side effects (arrow) presented with a decreased sPpa.Grahic Jump Location
Figure Jump LinkFigure 5 Individual changes in V̇o2max induced by the intake of bosentan in hypoxia. All the subjects, except one subject who experienced side effects (arrow), presented with an increased V̇o2max.Grahic Jump Location

The changes in hypoxic V̇o2max and in sPpa induced by the intake of bosentan were correlated (Fig 6). The correlation remained significant (r = 0.64; p < 0.05) after omission of the subject with side effects.

Figure Jump LinkFigure 6 Correlation between changes in sPpa (ΔsPpa) and changes in V̇o2max (ΔV̇o2max) induced by bosentan intake in subjects with acute hypoxia. The data point with increased sPpa and decreased V̇o2max belonged to the subject who experienced side effects. The correlation between ΔsPpa and ΔV̇o2max was significant (p = 0.01).Grahic Jump Location

The present results show that the intake of bosentan improves aerobic exercise capacity in relation to the inhibition of hypoxic pulmonary vasoconstriction in acutely hypoxic healthy subjects. This is likely explained by an increased convectional O2 transport to the exercising muscles due to a decreased right ventricular afterload. Bosentan is a dual ETA/ETB receptor antagonist, which is of established efficacy in the treatment of pulmonary arterial hypertension.6,18 The intake of dual ETA/ETB or specific ETA receptor blockers has been shown in invasive studies19,20 on subjects with a normal left ventricular function to be without significant effect on resting PVR. This was confirmed noninvasively in the present study with a refined measurement of PVR by multipoint Ppa-Q plots excluding a tonic effect of ET-1 on the normal human pulmonary circulation. Fluid retention after bosentan intake has been occasionally reported.6,7 Baseline echocardiographic findings remained unaltered in the present study, with, in particular, no change in right atrial or inferior vena cava dimensions, indirectly suggesting no hemodynamically relevant fluid retention.

Hypoxia in the present study increased sPpa by an average of 10 mm Hg and Q by an average of 0.5 L/min/m2. This is in the range of previously reported effects of short-term inspiratory hypoxia of similar severity, measured at right heart catheterization9 or at echocardiography4,5,10 in healthy volunteers. Bosentan partially inhibited this hypoxic response, which is in keeping with the results of previous studies on experimental animals21 and healthy volunteers who were rapidly taken to a high altitude.7 This observation, together with a previous report22 of increased circulating ET-1 levels in healthy subjects who had been exposed to high altitudes, supports the notion that ET-1 plays a role in the development of hypoxic pulmonary hypertension.

In the present study, there were no changes in arterial oxygenation or in the ventilatory response to exercise by the intake of bosentan, which is in agreement with our hypothesis that the drug would be specific for the pulmonary circulation and without effect on chemosensitivity or ventilation/perfusion matching. An improvement in Spo2 after the intake of bosentan had been previously noted7 after acute high-altitude exposure, but this effect was not sustained and would be unlikely to be explained by a decreased PVR or a change in ventilation. ET signaling has been previously reported to be involved in the increased peripheral chemosensitivity induced by intermittent chronic hypoxia in cats23 or chronic hypoxia in rats.24 However, this was not confirmed in a study8 of acutely hypoxic healthy volunteers, in whom bosentan did not affect sympathetic nervous system activity (as evaluated by microneurography) and did not influence the ventilatory responses to inspiratory hypoxia. Studies using the multiple-inert-gas-elimination technique have previously shown that pulmonary vascular tone improves ventilation/perfusion matching in patients with obliterative pulmonary hypertension25 and chronic lung disease,26 and also in healthy acutely hypoxic volunteers.27 An improvement in arterial blood oxygenation after the intake of sildenafil to decrease PVR has been reported in acutely hypoxic volunteers,4 but this could rather be explained by an improvement in lung diffusion,28 an increased mixed venous blood oxygenation because of an increased Q,5 or, more speculatively, preferential vasodilation in the better ventilated lung areas.4,5

Hypoxic exposure was associated with a decrease in aerobic exercise capacity, with decreases in maximum workload, V̇o2max, AT, maximum HR, V̇e, and O2 pulse, all of which are in keeping with previously reported exercise studies4,5,29 in subjects with similarly severe acute hypoxic or subacute conditions. Bosentan therapy improved V̇o2max, maximum workload, and O2 pulse, indicating improved aerobic exercise capacity. Maximum workload and V̇o2 at the AT did not change, but this was possibly due to a type II error related to the lesser stability of AT determination, increasing the signal-to-noise ratios.12,30 Bosentan therapy did not decrease V̇e/V̇co2 ratio, which typically increases in patients with severe pulmonary hypertension,31 and is sensitive to effective pharmacologic interventions in these patients.32 However, in the present study, pulmonary hypertension was mild with an average sPpa of 34 mm Hg, and hypoxic stimulation of the chemoreflex would be a confounding factor, making V̇e/V̇co2 ratio less specifically sensitive to the effects of increased PVR.

The only previously reported pharmacologic intervention to improve aerobic exercise capacity in hypoxic healthy subjects has been the intake of sildenafil. The drug improved both maximum workload and V̇o2max,4,5 but these effects were more significant in subjects with acute hypoxia than in those with chronic hypoxia. Furthermore, sildenafil therapy increased oxygenation in subjects with acute hypoxia and less so in those with chronic hypoxia; no correlation was found between any changes in V̇o2max and PVR.5 The present results suggest that bosentan therapy increased V̇o2max in the short term, specifically through a decrease in PVR, but whether this can be confirmed in subjects with more chronic hypoxic conditions is not known.

Hypoxic exposure decreases hypoxic exercise capacity by the combined effects of decreased arterial O2 content and maximum Q.1,2 The mechanisms of decreased maximum Q in hypoxia remain incompletely understood. Previously suggested explanations have been a decreased peripheral demand due to altered matching of diffusional and convectional O2 delivery processes,33 a decrease in venous return together with a decreased chronotropic reserve,34 a CNS limitation,35 and a limitation of right ventricular flow output because of a hypoxia-induced increase in PVR.4 The present demonstration of an inverse correlation between changes in sPpa and V̇o2max suggests a role for a limitation of right ventricular flow output, even though the latter was not directly measured.

Bosentan therapy improved V̇o2max in patients with hypoxia, but there was a proportionally smaller increase in maximum workload. It may also be noted that bosentan intake did not change V̇emax, and decreased the maximum RER. It is therefore possible that bosentan affected ventilation/perfusion matching through discrete effects on the distribution of either alveolar ventilation or perfusion. It is also possible that part of the improvement in exercise capacity would have been related to a change in the distribution of systemic perfusion. Hypoxia is associated with a redistribution of pulmonary blood flow to nonexercising muscles.2 ET-1 plays a role in the redistribution of systemic blood flow in exercising rats,36 swine,37 and humans.38 Thus, it is possible that part of the improvement in exercise capacity after bosentan intake in subjects with hypoxia would be accounted for by an improved perfusion of the exercising muscles.

Ppa in the present study was estimated from the velocity of tricuspid regurgitant jets. This method is well correlated to invasively measured Ppa in a variety of circumstances,39 with a particularly good agreement in healthy volunteers who were subjected to short-term high-altitude exposure,40 and it has been used during exercise tests as well as hypoxic stress tests to identify subjects with increased pulmonary pressor responses and susceptibility to high-altitude pulmonary edema.10 Q was estimated from aortic Doppler echocardiography. This method has been validated against Fick oximetry and thermodilution in exercising healthy volunteers.12

Acute hypoxic pulmonary hypertension in the present study was mild, as would be expected in healthy subjects.4,5,9,10 The sPpa hardly reached the upper limit of normal of 37 mm Hg as was previously defined in a large normal reference population of 3,790 subjects,41 even during exercise in hypoxia. It is therefore remarkable that only moderate hypoxic pulmonary hypertension in the present study appeared to determine a limitation in exercise capacity that could be partially reversed by bosentan therapy. However, exercise capacity remained markedly lower than that in patients in normoxia, indicating a relatively more important role for other factors than pulmonary hypertension or ET metabolism.

AT

anaerobic threshold

CPET

cardiopulmonary exercise test

ET

endothelin

Fio2

fraction of inspired oxygen

HR

heart rate

HRmax

maximum heart rate

mPpa

mean pulmonary artery pressure

Ppa

pulmonary artery pressure

Psa

systemic arterial pressure

PVR

pulmonary vascular resistance

Q

cardiac output

RER

respiratory exchange ratio

Spo2

pulse oximetric saturation

sPpa

systolic pulmonary artery pressure

co2

carbon dioxide output

e

minute ventilation

e max

maximum minute ventilation

o2

oxygen uptake

o2max

maximum oxygen uptake

We gratefully acknowledge Régine Bastin and Kathleen Retailleau for invaluable help with the echocardiographic measurements.

Fulco CS, Rock PB, Cymerman A. Maximal and submaximal exercise performance at altitude. Aviat Space Environ Med. 1998;69:793-801. [PubMed]
 
Calbet JA, Boushel R, Radegran G, et al. Why is V̇o2max after altitude acclimatization still reduced despite normalization of arterial O2content? Am J Physiol Regul Integr Comp Physiol. 2003;284:R304-R316. [PubMed]
 
Rubin LJ, Naeije R. Sildenafil for enhanced performance at high altitude? Ann Intern Med. 2004;141:233-235. [PubMed]
 
Ghofrani HA, Reichenberger F, Kohstall MG, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med. 2004;141:169-177. [PubMed]
 
Faoro V, Lamotte M, Deboeck G, et al. Effects of sildenafil on hypoxic exercise capacity in normal subjects. High Alt Med Biol. 2007;8:155-163. [PubMed] [CrossRef]
 
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903. [PubMed]
 
Modesti PA, Vanni S, Morabito M, et al. Role of endothelin-1 in exposure to high altitude: Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation. 2006;114:1410-1416. [PubMed]
 
Gujic M, Houssiere A, Xhaet O, et al. Does endothelin play a role in chemoreception during acute short term hypoxia in normal men? Chest. 2007;131:1467-1472. [PubMed]
 
Maggiorini M, Melot C, Pierre S, et al. High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation. 2001;103:2078-2083. [PubMed]
 
Grunig E, Mereles D, Hildebrandt W, et al. Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema. J Am Coll Cardiol. 2000;35:980-987. [PubMed]
 
Yamaya Y, Boogard HJ, Wagner PD, et al. Validity of pulse oximetry during maximal exercise in normoxia, hypoxia, and hyperoxia. J Appl Physiol. 2002;92:162-168. [PubMed]
 
Christie J, Sheldahl LM, Tristani FE, et al. Determination of stroke volume and cardiac output during exercise: comparison of two-dimensional and Doppler echocardiography, Fick oximetry and thermodilution. Circulation. 1987;76:539-547. [PubMed]
 
Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation. 1984;70:657-662. [PubMed]
 
Chemla D, Castelain V, Humbert M, et al. New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest. 2004;126:1313-1317. [PubMed]
 
Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation. 1999;3rd ed Baltimore, MD Lippincott Williams & Wilkins:143-164
 
Poon CS. Analysis of linear and mildly nonlinear relationships using pooled subject data. J Appl Physiol. 1988;64:854-858. [PubMed]
 
Winer BJ, Brown DR, Michels KM. Statistical principles in experimental design. 1991;3rd ed New York, NY McGraw-Hill:220-283
 
Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436. [PubMed]
 
Fleisch M, Sütsch, Yan XW, et al. Systemic, pulmonary, and renal hemodynamic effects of endothelin ET(A/B)-receptor blockade in patients with maintained left ventricular function. J Cardiovasc Pharmacol. 2000;36:302-309. [PubMed]
 
Ooi H, Colucci WS, Givertz MM. Endothelin mediates increased pulmonary vascular tone in patients with heart failure: demonstration by direct intrapulmonary infusion of sitaxsentan. Circulation. 2002;106:1618-1621. [PubMed]
 
Chen SJ, Chen IF, Meng QC, et al. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol. 1995;79:2122-2131. [PubMed]
 
Goerre S, Wenk M, Bartsch P, et al. Endothelin-1 in pulmonary hypertension associated with high-altitude exposure. Circulation. 1995;91:359-364. [PubMed]
 
Rey S, Corthorn J, Chacxon C, et al. Expression and immunolocalisation of endothelin peptides and its receptors, ETA and ETB, in the carotid body exposed to chronic intermittent hypoxia. J Histochem Cytochem. 2007;55:167-174. [PubMed]
 
Chen J, He L, Liu X, et al. Effect on the endothelin receptor antagonist bosentan on chronic hypoxia-induced morphological and physiological changes in the rat carotid body. Am J Physiol Lung Cell Mol Physiol. 2007;292:L1257-L1262. [PubMed]
 
Dantzker DR, Bower JS. Pulmonary vascular tone improves VA/Q matching in obliterative pulmonary hypertension. J Appl Physiol. 1981;51:607-613. [PubMed]
 
Mélot C, Hallemans R, Mols P, et al. Deleterious effects of nifedipine on pulmonary gas exchange in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1984;130:612-616. [PubMed]
 
Mélot C, Naeije R, Hallemans R, et al. Hypoxic pulmonary vasoconstriction and pulmonary gas exchange in normal man. Respir Physiol. 1987;68:11-27. [PubMed]
 
Guazzi M, Tumminello G, Di Marco F, et al. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol. 2004;44:2339-2348. [PubMed]
 
Faoro V, Huez S, Giltaire S, et al. Acetazolamide improves aerobic exercise capacity but not pulmonary hypertension at high altitudes. J Appl Physiol. 2007;103:1161-1165. [PubMed]
 
Fleg JL, Piña IL, Balady GJ, et al. Assessment of functional capacity in clinical and research applications: an advisory from the Committee on Exercise, Rehabilitation, and Prevention, Council on Clinical Cardiology, American Heart Association. Circulation. 2000;102:1591-1597. [PubMed]
 
Sun XG, Hansen EJ, Oudiz R, et al. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation. 2001;104:429-435. [PubMed]
 
Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation. 2002;106:319-324. [PubMed]
 
Wagner PD. Reduced maximal cardiac output at altitude: mechanisms and significance. Respir Physiol. 2000;120:1-11. [PubMed]
 
Reeves JT, Groves BM, Sutton JR, et al. Operation Everest II: preservation of cardiac function at extreme altitude. J Appl Physiol. 1987;63:531-539. [PubMed]
 
Kayser B. Exercise begins and ends in the brain. Eur J Appl Physiol. 2003;90:411-419. [PubMed]
 
Maeda S, Miyauchi T, Iemitsu M, et al. Involvement of endogenous endothelin-1 in exercise-induced redistribution of tissue blood flow: an endothelin receptor antagonist reduces the distribution. Circulation. 2002;106:2188-2193. [PubMed]
 
Merkus D, Houweling B, Mirza A, et al. Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation. Cardiovasc Res. 2003;59:745-754. [PubMed]
 
Wray DW, Nishiyama SK, Donato AJ, et al. Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans. Am J Physiol Heart Circ Physiol. 2007;293:H2550-H2556. [PubMed]
 
Naeije R, Torbicki A. More on the noninvasive diagnosis of pulmonary hypertension: Doppler echocardiography revisited [editorial]. Eur Respir J. 1995;8:1445-1449. [PubMed]
 
Allemann Y, Sartori C, Lepori M, et al. Echographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude. Am J Physiol Heart Circ Physiol. 2000;279:H2013-H2016. [PubMed]
 
McQuillan BM, Picard MH, Leavitt M, et al. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation. 2001;104:2797-2802. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Pooled mPpa vs cardiac index relationships in 11 healthy subjects before (■) and during hypoxic breathing (♦). The calculated regressions are represented by full and dotted lines, respectively. Hypoxia shifted pressure-flow relationships to higher pressures, indicating hypoxic pulmonary vasoconstriction.Grahic Jump Location
Figure Jump LinkFigure 2 Pooled mPpa vs cardiac index relationships in 11 healthy subjects before (■) and after bosentan intake (□) in normoxia. The calculated regressions are represented by full and stippled lines, respectively. Bosentan had no effect on pressure-flow relationships, indicating an absence of effect on resting pulmonary vascular tone.Grahic Jump Location
Figure Jump LinkFigure 3 Pooled mPpa vs cardiac index relationships in 11 healthy subjects before (♦) and after bosentan intake (◇) in hypoxia. The calculated regressions are represented by full and dotted lines, respectively. Despite individual variability, bosentan shifted pressure-flow relationships to lower pressures, indicating the inhibition of hypoxic pulmonary vasoconstriction.Grahic Jump Location
Figure Jump LinkFigure 4 Individual changes in sPpa induced by the intake of bosentan in hypoxia. All the subjects except one with side effects (arrow) presented with a decreased sPpa.Grahic Jump Location
Figure Jump LinkFigure 5 Individual changes in V̇o2max induced by the intake of bosentan in hypoxia. All the subjects, except one subject who experienced side effects (arrow), presented with an increased V̇o2max.Grahic Jump Location
Figure Jump LinkFigure 6 Correlation between changes in sPpa (ΔsPpa) and changes in V̇o2max (ΔV̇o2max) induced by bosentan intake in subjects with acute hypoxia. The data point with increased sPpa and decreased V̇o2max belonged to the subject who experienced side effects. The correlation between ΔsPpa and ΔV̇o2max was significant (p = 0.01).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Effects of Bosentan on Hemodynamics and Oxygen Saturation in Normoxia and in Hypoxia in Normal Subjects at Rest*

*Values are given as the mean ± SD. Hypoxia = Fio2 0.12.

†p < 0.05 vs low altitude.

‡p < 0.001 vs low altitude.

§p < 0.01 vs low altitude.

‖p < 0.01 vs placebo in high altitude.

Table Graphic Jump Location
Table 2 Effects of Bosentan on Cardiopulmonary Exercise Variables in Normoxia and in Hypoxia in Healthy Subjects*

*Values are given as the mean ± SD. Workload max = maximum workload; RERmax = maximum RER. See Table 1 for abbreviation not used in the text.

†p < 0.001 vs low altitude.

‡p < 0.05 vs placebo in acute hypoxia.

§p < 0.01 vs placebo in acute hypoxia.

‖p < 0.05 vs low altitude.

¶p < 0.01 vs low altitude.

References

Fulco CS, Rock PB, Cymerman A. Maximal and submaximal exercise performance at altitude. Aviat Space Environ Med. 1998;69:793-801. [PubMed]
 
Calbet JA, Boushel R, Radegran G, et al. Why is V̇o2max after altitude acclimatization still reduced despite normalization of arterial O2content? Am J Physiol Regul Integr Comp Physiol. 2003;284:R304-R316. [PubMed]
 
Rubin LJ, Naeije R. Sildenafil for enhanced performance at high altitude? Ann Intern Med. 2004;141:233-235. [PubMed]
 
Ghofrani HA, Reichenberger F, Kohstall MG, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med. 2004;141:169-177. [PubMed]
 
Faoro V, Lamotte M, Deboeck G, et al. Effects of sildenafil on hypoxic exercise capacity in normal subjects. High Alt Med Biol. 2007;8:155-163. [PubMed] [CrossRef]
 
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903. [PubMed]
 
Modesti PA, Vanni S, Morabito M, et al. Role of endothelin-1 in exposure to high altitude: Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation. 2006;114:1410-1416. [PubMed]
 
Gujic M, Houssiere A, Xhaet O, et al. Does endothelin play a role in chemoreception during acute short term hypoxia in normal men? Chest. 2007;131:1467-1472. [PubMed]
 
Maggiorini M, Melot C, Pierre S, et al. High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation. 2001;103:2078-2083. [PubMed]
 
Grunig E, Mereles D, Hildebrandt W, et al. Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema. J Am Coll Cardiol. 2000;35:980-987. [PubMed]
 
Yamaya Y, Boogard HJ, Wagner PD, et al. Validity of pulse oximetry during maximal exercise in normoxia, hypoxia, and hyperoxia. J Appl Physiol. 2002;92:162-168. [PubMed]
 
Christie J, Sheldahl LM, Tristani FE, et al. Determination of stroke volume and cardiac output during exercise: comparison of two-dimensional and Doppler echocardiography, Fick oximetry and thermodilution. Circulation. 1987;76:539-547. [PubMed]
 
Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation. 1984;70:657-662. [PubMed]
 
Chemla D, Castelain V, Humbert M, et al. New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest. 2004;126:1313-1317. [PubMed]
 
Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation. 1999;3rd ed Baltimore, MD Lippincott Williams & Wilkins:143-164
 
Poon CS. Analysis of linear and mildly nonlinear relationships using pooled subject data. J Appl Physiol. 1988;64:854-858. [PubMed]
 
Winer BJ, Brown DR, Michels KM. Statistical principles in experimental design. 1991;3rd ed New York, NY McGraw-Hill:220-283
 
Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436. [PubMed]
 
Fleisch M, Sütsch, Yan XW, et al. Systemic, pulmonary, and renal hemodynamic effects of endothelin ET(A/B)-receptor blockade in patients with maintained left ventricular function. J Cardiovasc Pharmacol. 2000;36:302-309. [PubMed]
 
Ooi H, Colucci WS, Givertz MM. Endothelin mediates increased pulmonary vascular tone in patients with heart failure: demonstration by direct intrapulmonary infusion of sitaxsentan. Circulation. 2002;106:1618-1621. [PubMed]
 
Chen SJ, Chen IF, Meng QC, et al. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol. 1995;79:2122-2131. [PubMed]
 
Goerre S, Wenk M, Bartsch P, et al. Endothelin-1 in pulmonary hypertension associated with high-altitude exposure. Circulation. 1995;91:359-364. [PubMed]
 
Rey S, Corthorn J, Chacxon C, et al. Expression and immunolocalisation of endothelin peptides and its receptors, ETA and ETB, in the carotid body exposed to chronic intermittent hypoxia. J Histochem Cytochem. 2007;55:167-174. [PubMed]
 
Chen J, He L, Liu X, et al. Effect on the endothelin receptor antagonist bosentan on chronic hypoxia-induced morphological and physiological changes in the rat carotid body. Am J Physiol Lung Cell Mol Physiol. 2007;292:L1257-L1262. [PubMed]
 
Dantzker DR, Bower JS. Pulmonary vascular tone improves VA/Q matching in obliterative pulmonary hypertension. J Appl Physiol. 1981;51:607-613. [PubMed]
 
Mélot C, Hallemans R, Mols P, et al. Deleterious effects of nifedipine on pulmonary gas exchange in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1984;130:612-616. [PubMed]
 
Mélot C, Naeije R, Hallemans R, et al. Hypoxic pulmonary vasoconstriction and pulmonary gas exchange in normal man. Respir Physiol. 1987;68:11-27. [PubMed]
 
Guazzi M, Tumminello G, Di Marco F, et al. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol. 2004;44:2339-2348. [PubMed]
 
Faoro V, Huez S, Giltaire S, et al. Acetazolamide improves aerobic exercise capacity but not pulmonary hypertension at high altitudes. J Appl Physiol. 2007;103:1161-1165. [PubMed]
 
Fleg JL, Piña IL, Balady GJ, et al. Assessment of functional capacity in clinical and research applications: an advisory from the Committee on Exercise, Rehabilitation, and Prevention, Council on Clinical Cardiology, American Heart Association. Circulation. 2000;102:1591-1597. [PubMed]
 
Sun XG, Hansen EJ, Oudiz R, et al. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation. 2001;104:429-435. [PubMed]
 
Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation. 2002;106:319-324. [PubMed]
 
Wagner PD. Reduced maximal cardiac output at altitude: mechanisms and significance. Respir Physiol. 2000;120:1-11. [PubMed]
 
Reeves JT, Groves BM, Sutton JR, et al. Operation Everest II: preservation of cardiac function at extreme altitude. J Appl Physiol. 1987;63:531-539. [PubMed]
 
Kayser B. Exercise begins and ends in the brain. Eur J Appl Physiol. 2003;90:411-419. [PubMed]
 
Maeda S, Miyauchi T, Iemitsu M, et al. Involvement of endogenous endothelin-1 in exercise-induced redistribution of tissue blood flow: an endothelin receptor antagonist reduces the distribution. Circulation. 2002;106:2188-2193. [PubMed]
 
Merkus D, Houweling B, Mirza A, et al. Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation. Cardiovasc Res. 2003;59:745-754. [PubMed]
 
Wray DW, Nishiyama SK, Donato AJ, et al. Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans. Am J Physiol Heart Circ Physiol. 2007;293:H2550-H2556. [PubMed]
 
Naeije R, Torbicki A. More on the noninvasive diagnosis of pulmonary hypertension: Doppler echocardiography revisited [editorial]. Eur Respir J. 1995;8:1445-1449. [PubMed]
 
Allemann Y, Sartori C, Lepori M, et al. Echographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude. Am J Physiol Heart Circ Physiol. 2000;279:H2013-H2016. [PubMed]
 
McQuillan BM, Picard MH, Leavitt M, et al. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation. 2001;104:2797-2802. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543