(Circulation. 1995;91:359-364.)
© 1995 American Heart Association, Inc.
Articles |
Endothelin-1 in Pulmonary Hypertension Associated With High-Altitude Exposure
From Internal Medicine, Kantonsspital, Chur, Switzerland (S.G., W.H.R.); the Department of Medicine, Division of Clinical Pharmacology, University Hospital, Basel, Switzerland (M.W., T.F.L.); the Departments of Sports Medicine (P.B., E.H.) and Cardiology (F.N.), University of Heidelberg, Germany; and Stadtspital Triemli, Zürich, Switzerland (O.O.).
Correspondence to W. Reinhart, MD, Internal Medicine, Kantonsspital, CH-7000 Chur, Switzerland.
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Abstract |
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Background Endothelin-1 is involved in chronic pulmonary hypertension. Its role in acute pulmonary hypertension due to hypoxia in humans is not clear. We therefore studied the influence of hypoxia caused by exposure to high altitude on plasma endothelin-1 levels, arterial blood gases, and pulmonary arterial pressure in subjects taking nifedipine or placebo.
Methods and Results Twenty-two healthy volunteers were investigated at low altitude (490 m) and high altitude (4559 m). Arterial blood gases were analyzed immediately, endothelin-1 was measured by radioimmunoassay, and pulmonary artery pressure was assessed by Doppler echocardiography. After baseline investigations, the mountaineers were allocated in a randomized double-blind fashion to receive either placebo or nifedipine (20 mg TID) during rapid ascent to high altitude within 22 hours. Tests were repeated at the high-altitude research laboratories located in the Capanna "Regina Margherita" (Italy, 4559 m). Plasma endothelin-1 was increased twofold at high altitude (5.9±2.2 pg/mL compared with 2.9±1.1 pg/mL, P<.05), was inversely related to arterial PO2 (r=-.46, P<.001), and correlated with pulmonary artery pressure (r=.52, P<.002). At high altitude, arterial endothelin-1 was lower (4.3±1.6 pg/mL) than venous endothelin-1 (5.9±2.2 pg/mL, P<.001), indicating either predominant production in the venous vasculature or pronounced clearance in the pulmonary circulation. The calcium antagonist nifedipine, which lowered pulmonary artery pressure at high altitude (32±5 versus 42±11 mm Hg, P<.05), had no influence on plasma endothelin-1 levels. The administration of 35% O2 at high altitude normalized arterial PO2, tended to decrease endothelin-1, and decreased pulmonary artery pressure accordingly.
Conclusions We conclude that plasma endothelin-1 is increased at high altitude, but whether or not it represents an important pathogenetic factor for pulmonary hypertension remains to be investigated.
Key Words: endothelin • hypoxia • calcium channels • arteries • pressure
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Introduction |
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Endothelin-1 (ET-1) is a very potent vasoconstrictor peptide produced by endothelial cells1 that seems to be intimately involved in the pathogenesis of chronic pulmonary hypertension.2 3 It is currently not clear whether high ET-1 plasma levels are mediators of the disease or only markers.2 An interesting model to study this question further is acute pulmonary artery hypertension due to hypoxia, eg, during exposure to high altitude. It has been found that rats exposed to hypoxia had increased ET-1 that inversely correlated with arterial PO24 and that was due to increased ET-1 gene expression.5 Experiments in other animal species, however, failed to confirm a relation between hypoxia and ET-16 or a role of ET-1 as a mediator of hypoxic vasoconstriction.7 In children with pulmonary hypertension undergoing cardiac catheterization, ET-1 levels correlated with vasoreactivity during acute hypoxia.8 This has not yet been studied in healthy humans.
In the present study, we analyzed the influence of an ascent of healthy volunteers to high altitude and the effect of restoring arterial PO2 to sea-level values at high altitude on blood gases, venous and arterial ET-1 levels, and pulmonary artery pressure as assessed by noninvasive Doppler echocardiography. The subjects were taking either nifedipine or placebo in a double-blind, randomized fashion, which enabled us to examine whether the decrease in pulmonary artery pressure under nifedipine9 is associated with a decrease in plasma levels of ET-1.
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Methods |
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Twenty-two mountaineers (14 men and 8 women, 21 to 54 years old) were investigated in the context of a study in 27 subjects on the prophylactic effect of nifedipine in acute mountain sickness.10 The study had been approved by the ethical committee of the University of Zürich, and the volunteers gave their informed consent. These subjects were not susceptible to high-altitude pulmonary edema. None of the individuals took drugs other than paracetamol (n=10). Four of them did smoke. None of the subjects suffered from vascular diseases, particularly not Raynaud's syndrome. Five of the initial 27 subjects dropped out of our study because of problems with ET-1 extraction in the laboratory. Baseline investigations at low altitude (Zürich, Switzerland, 490 m) included transthoracic Doppler echocardiography and venous and arterial blood sampling. The subjects were then assigned in a double-blind fashion to receive either placebo or nifedipine (Adalat retard, 20 mg) starting with 20 mg on days -3 and -2, 20 mg BID on day -1, and 20 mg TID during ascent and while staying at high altitude. The mountaineers ascended from 1130 to 4559 m within 22 hours, with transportation to 3200 m by cable car (Punta Indren, Italy) and an overnight stay at 3611 m. At 4559 m, echocardiography and blood sampling as described below were repeated in the high-altitude research laboratory at the Capanna "Regina Margherita" by the same physicians on 3 consecutive days.
Doppler echocardiography was done with a real-time phased-array sector scanner (Hewlett Packard 77020 AC) with continuous-wave and color Doppler facilities. Pulmonary artery pressure was estimated from the pressure gradient between right atrium and ventricle with the help of continuous-wave Doppler and the clinically determined jugular venous pressure.11 Estimation of right ventricular systolic pressure by continuous-wave Doppler has been shown to yield information comparable to cardiac catheterization, particularly with increased right ventricular pressure, with which approximately 80% of patients have analyzable Doppler tricuspid regurgitant velocities.11
Arterial blood gas analysis was performed immediately after sampling (278 blood gas system, Ciba Corning Diagnostics). For the determination of ET-1 plasma levels, blood samples anticoagulated with EDTA were drawn from an antecubital vein and radial artery, immediately put on ice, and centrifuged at 1500g for 10 minutes, and the plasma was snap-frozen in liquid nitrogen. Plasma ET-1 levels were measured by radioimmunoassay after solid-phase extraction using SepPak C18 cartridges (Millipore-Waters) similar to the method of Sørensen.12 Extraction recoveries were 76%. For the radioimmunoassay, an antiserum against ET-1 from Peninsula Laboratories was used. After preincubation of the samples with antiserum for 24 hours, 125I-labeled ET-1 (Biomedica) was added, and the incubation was continued for another 24 hours. Bound and free ET-1 were separated with a second antibody system (Peninsula Laboratories). The sensitivity of the test was 0.7 pg/mL.
Data were expressed as mean±SD. Missing values (echocardiography and blood gas analysis) on day 3 at high altitude were due to two breakdowns of the power supply; other isolated missing values were due to inadequate blood sampling, insufficient Doppler spectra for the assessment of pulmonary artery pressure, or one dropout from the study because of administration of dexamethasone for acute mountain sickness. Statistical analysis was done with one-way ANOVA; in the case of only two groups, by Student's t test. A linear regression model was used to study interdependency. A two-tailed value of P<.05 was considered to be significant.
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Results |
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None of the subjects developed high-altitude pulmonary edema. Acute mountain sickness was diagnosed in 6 subjects on placebo and 5 subjects on nifedipine. Plasma ET-1 levels were increased twofold on the first day at high altitude (Fig 1
). No relation was
found between ET-1 levels and presence or absence of acute mountain
sickness. Over the next 2 days at high altitude, plasma ET-1 tended to
decrease but remained elevated compared with low-altitude values (Table
1). Venous and arterial levels of ET-1 were similar at
low altitude (2.9±1.1 and 2.7±1.4 pg/mL, respectively); at high
altitude, however, venous ET-1 values were significantly higher than
arterial values (5.9±2.2 versus 4.3±1.6 pg/mL,
P<.001),
which is illustrated in Fig 2. The prophylactic
administration of nifedipine during ascent and at altitude influenced
neither venous nor arterial plasma ET-1 levels. The four smokers had
slightly but not significantly higher ET-1 levels than nonsmokers (at
low altitude, 3.7±1.1 pg/mL for smokers versus 2.8±1.1 pg/mL for
nonsmokers, P=.13, and at high altitude, 7.1±2.7 pg/mL
for
smokers versus 5.6±2.0 pg/mL for nonsmokers, P=.21).
There
were no significant differences in arterial
PO2 and pulmonary pressure between smoking
and nonsmoking individuals at either low or high altitude.
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) were taking nifedipine (20
mg TID) during ascent and while staying at high altitude; 10 subjects
received placebo (
).
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Pulmonary arterial pressure was increased at high altitude in
subjects receiving nifedipine (20 mg TID) to a significantly lower
extent than in those receiving placebo (Table 1
). Data on
pulmonary
artery pressure were therefore analyzed separately for placebo and
nifedipine. A positive correlation existed between pulmonary arterial
pressure and either venous plasma ET-1 (all data:
y=22.55+2.19x, r=.40,
n=61,
P<.002; subjects on nifedipine excluded: r=.52,
n=36, P<.002; Fig 3) or arterial ET-1 (all
data: y=18.64+2.96x, r=.60,
n=29, P<.001; subjects on nifedipine excluded:
y=22.70+2.47x, r=.55,
n=13,
P<.05). Systemic arterial blood pressure was unaffected by
high altitude and nifedipine treatment with the exception of day 2,
when values with nifedipine were lower than with placebo (not shown;
see Reference 10).
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) and of subjects receiving placebo at high
altitude (
Blood gas analysis revealed the expected decreases in
PO2 and PCO2 as
well as an increase in pH (Table 2). No difference was
found between nifedipine and placebo. The corresponding
PO2 and ET-1 values at low and high altitude
for each individual are shown in Fig 4. With the
exception of the same subject as in Fig 1, the decrease in
PO2 was followed by an increase in venous
ET-1. Negative correlations were found between all data of
PO2 and ET-1
(y=6.77-0.04x, r=-.44,
n=74, P<.001, and
y=5.18-0.02x, r=-.39,
n=36,
P<.05 for venous and arterial ET-1, respectively) and
between PCO2 and ET-1
(y=10.78-0.20x,
r=-.53, P<.001); a positive correlation was
found between pH and ET-1, which is shown in Fig 5.
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On day 2 at high altitude, a descent to low altitude was simulated by
breathing 35% oxygen (oxygen content at sea level) through a mask for
30 minutes. This simulated descent normalized
PO2 (89.5±7.6 mm Hg) and decreased
pulmonary arterial pressure significantly, from 38±12 to 34±10
mm Hg
(P<.005) for all individuals and from 47±11 to 40±9
mm Hg (P<.005) for individuals on placebo. At the same
time, ET-1 tended to decrease also (all data: from 4.9±1.8 to
4.5±1.5
pg/mL, P=.06; individuals without nifedipine: from
5.l±1.9
to 4.5±1.4 pg/mL; P=.12). In addition, as shown in Fig
6, the decrease in ET-1 levels correlated significantly
with the decrease in pulmonary arterial pressure (all data:
r=.61, P<.05; individuals without nifedipine:
r=.73, P<.05).
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Discussion |
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The results of this study demonstrate that the degree of hypoxia-induced acute pulmonary hypertension, assessed by the indirect method of Doppler echocardiography (which may explain the relatively large scatter of the data), correlates with increased plasma ET-1 levels in healthy mountaineers. Although the increase in ET-1 levels was most marked 2 hours after arrival at high altitude, the levels remained high during the sojourn at 4559 m. This time course underscores that the increase in ET-1 associated with high altitude–induced pulmonary hypertension is persistent.
This relation could be causal or may represent an epiphenomenon. A
causal relation, ie, that hypoxia at high altitude induces pulmonary
artery hypertension by the release of ET-1, is a distinct possibility.
Such an interpretation is supported by the following findings: (1) ET-1
is able to cause profound and persistent vasoconstriction, particularly
in the pulmonary circulation.13 14 Thus, increased
local
levels of the peptide could mediate pulmonary hypertension. (2) In
isolated rat blood vessels and cultured human endothelial cells,
hypoxia induces both ET-1 gene expression and secretion of the
peptide.15 (3) This study revealed a negative correlation
between PO2 and ET-1 plasma levels in humans.
(4) The decrease of pulmonary artery pressure during O2
administration at high altitude was accompanied by a drop in plasma
ET-1 levels. The normalization of both pulmonary pressure and plasma
ET-1 levels in response to oxygen breathing at high altitude supports
the concept of a causal link between the two variables. Nevertheless,
since the correlation between PO2 and ET-1
levels was not highly significant (two-tailed probability value of
P
.05), other factors must also be considered.
Besides hypoxia, changes in pH occurring at high altitude might also be important. The relation between arterial pH and plasma ET-1 levels suggests that alkalosis may contribute to ET-1 release. This question, however, could be answered only by investigating patients with acid-base imbalance without hypoxia. Earlier studies in isolated dog aortas16 and blood samples drawn from human umbilical veins17 have indicated the opposite, ie, that acidosis rather than alkalosis may stimulate ET-1 secretion.
Another relevant stimulus for ET-1 production might be cold. Although certain authors18 found an increase in ET-1 levels after exposure of the forearm to severe cold (0°C), we were unable to confirm this observation (unpublished observation). Furthermore, the temperature at the high-altitude laboratory did not fall below 20°C (68°F). Hence, cold is rather unlikely to contribute to the increase in ET-1 observed at high altitude.
Physical exercise associated with the ascent to high altitude also could have stimulated ET-1 production via either an increase in blood flow (and consecutive shear stress) or a release of catecholamines. The effect of shear stress on the release of ET-1 is at present controversial, with some investigators observing an increase19 20 but others a downregulation of ET-1.21 22 Concerning an eventual influence of catecholamines, a high-altitude sojourn is indeed associated with increased norepinephrine plasma concentrations.23 24 Nevertheless, available data on the influence of catecholamines on ET-1 levels are contradictory: although in vitro marked induction of preendothelin mRNA by adrenaline has been reported,1 no correlation between endothelin and plasma catecholamine concentrations has been observed in patients with systemic hypertension and diabetes25 as well as during open-heart surgery.26 The fact that in this study, plasma ET-1 levels at high altitude were measured after 2 hours of rest, when plasma catecholamines are expected to be back to baseline values,27 28 makes an important contribution of these hormones unlikely. In addition, plasma ET-1 levels remained high on days 2 and 3, when blood sampling was done in the morning after an overnight rest and before any physical effort. Finally, a study in patients with chronic heart failure did not reveal any influence of exercise on ET-1 levels.29 Thus, an important contribution of exercise to the observed increase in plasma endothelin-1 at high altitude is unlikely.
Another confounding factor might be cigarette smoking, since it may further promote hypoxia at high altitude. In fact, in this study, smoking individuals had slightly but not significantly higher ET-1 levels than nonsmokers. Because arterial PO2 values of smokers did not differ from those of nonsmokers, a direct effect of smoking and its components on ET-1 plasma concentrations is possible. To the best of our knowledge, no data are available on the effect of cigarette smoking on ET-1 levels.
An interaction of antihypertensive or vasodilator drugs with the results of this study can be ruled out, since none of the individuals took medications other than paracetamol except nifedipine if randomized to the nifedipine group (see below). Vascular diseases associated with increased ET-1 levels,30 31 particularly Raynaud's syndrome, were not present among the investigated subjects.
Interestingly, the calcium antagonist nifedipine did not affect plasma ET-1 levels, although ET-1 production and release from cultured cells1 32 as well as intact blood vessels is calcium dependent.32 The increase in calcium in endothelial cells, however, is derived primarily from intracellular sources (via activation of phospholipase C and inositol triphosphate32 ) and not through voltage-operated calcium channels, which are not expressed in the endothelial cell membrane. On the other hand, the calcium antagonist lowered pulmonary systolic pressure in treated subjects. Hence, nifedipine interacts with the action, not the production, of the peptide.
Another remarkable observation in this study was the fact that at high altitude, venous ET-1 levels were significantly higher than arterial ET-1 levels. This would suggest that the venous vasculature contributed more to the increase in plasma ET-1 levels at high altitude than did the arterial side, which agrees with the observation of Elton et al5 that hypoxia increased ET-1 mRNA in right atrium and lung but not in the systemic vascular bed. An alternative explanation, however, might be a more pronounced clearance of ET-1 during passage through the pulmonary circulation at high altitude. Indeed, the lungs play an important role in the metabolism of circulating ET-1. Together with the liver and the kidneys, the lungs are known to be primary sites of ET-1 extraction,33 which is true for healthy human subjects but not for diseased lungs, eg, in primary pulmonary hypertension.2 Hence, these results obtained in healthy mountaineers would suggest that normal human lungs extract more ET-1 at high altitude than they do at low altitude. It is possible that the peripheral pulmonary vasoconstriction is associated with slower local flow rates and therefore a higher extraction of circulating peptide due to prolonged exposure to the pulmonary microcirculation.
Thus, in summary, high altitude is associated with increased plasma ET-1 levels in healthy mountaineers; the stimulus is probably hypoxia. The correlation of changes in plasma ET-1 levels and PO2 as well as systolic pulmonary pressure suggests that ET-1 may represent a pathogenetic factor for pulmonary hypertension. Definitive proof for a causal role of ET-1 in pulmonary hypertension associated with high-altitude exposure, however, awaits the results of studies with specific ET-receptor antagonists, which will become available in the near future.34 Indeed, the administration of ET-1–receptor antagonists in rats with endothelin-induced pulmonary hypertension lowered systolic pulmonary pressure.35 36
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Acknowledgments |
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This study was supported by grants from the Swiss National Research Foundation (33729.92, 32-32541.91, and 32-36575.92) and the Sandoz Foundation. We thank the Italian Alpine Club (CAI Varallo) for the hospitality at the Capanna "Regina Margherita."
Received June 28, 1994; accepted August 2, 1994.
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 X. Wang, M. Tong, S. Chinta, J. U. Raj, and Y. Gao Hypoxia-induced reactive oxygen species downregulate ETB receptor-mediated contraction of rat pulmonary arteries Am J Physiol Lung Cell Mol Physiol, March 1, 2006; 290(3): L570 - L578. [Abstract] [Full Text] [PDF]
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 W. Johnson, A. Nohria, L. Garrett, J. C. Fang, J. Igo, M. Katai, P. Ganz, and M. A. Creager Contribution of endothelin to pulmonary vascular tone under normoxic and hypoxic conditions Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H568 - H575. [Abstract] [Full Text] [PDF]
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T. F. Luscher and M. Barton Endothelins and Endothelin Receptor Antagonists : Therapeutic Considerations for a Novel Class of Cardiovascular Drugs Circulation, November 7, 2000; 102(19): 2434 - 2440. [Abstract] [Full Text] [PDF]
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T. C. Carpenter and K. R. Stenmark Endothelin receptor blockade decreases lung water in young rats exposed to viral infection and hypoxia Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L547 - L554. [Abstract] [Full Text] [PDF]
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 L. Dumont, C. Mardirosoff, and M. R Tramèr Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review BMJ, July 29, 2000; 321(7256): 267 - 272. [Abstract] [Full Text]
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 B Prendergast, D E Newby, L E Wilson, D J Webb, and P S Mankad Early therapeutic experience with the endothelin antagonist BQ-123 in pulmonary hypertension after congenital heart surgery Heart, October 1, 1999; 82(4): 505 - 508. [Abstract] [Full Text] [PDF]
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C. Sartori, L. Vollenweider, B.-M. Loffler, A. Delabays, P. Nicod, P. Bartsch, and U. Scherrer Exaggerated Endothelin Release in High-Altitude Pulmonary Edema Circulation, May 25, 1999; 99(20): 2665 - 2668. [Abstract] [Full Text] [PDF]
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L.-W. Chen, C.-F. Chen, and Y.-L. Lai Chronic activation of neurokinin-1 receptor induces pulmonary hypertension in rats Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1543 - H1551. [Abstract] [Full Text] [PDF]
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L. V. d'Uscio, S. Shaw, M. Barton, and T. F. Luscher Losartan but Not Verapamil Inhibits Angiotensin II–Induced Tissue Endothelin-1 Increase : Role of Blood Pressure and Endothelial Function Hypertension, June 1, 1998; 31(6): 1305 - 1310. [Abstract] [Full Text] [PDF]
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 E. Wight, C. F. Kung, P. Moreau, H. Takase, and T. F. Luscher Chronic Blockade of Nitric Oxide-Synthase and Endothelin Receptors During Pregnancy in the Rat: Effect on Pregnancy Outcome Reproductive Sciences, May 1, 1998; 5(3): 132 - 139. [Abstract] [PDF]
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K. Stangl, T. Dschietzig, M. Laule, K. Alexiou, K. D. Wernecke, and G. Baumann Pulmonary Big Endothelin Affects Coronary Tone and Leads to Enhanced, ETA-Mediated Coronary Constriction in Early Endothelial Dysfunction Circulation, November 4, 1997; 96(9): 3192 - 3200. [Abstract] [Full Text]
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 R. M. Smith, T. J. Brown, A. G. Roach, K. I. Williams, and B. Woodward Evidence for Endothelin Involvement in the Pulmonary Vasoconstrictor Response to Systemic Hypoxia in the Isolated Rat Lung J. Pharmacol. Exp. Ther., November 1, 1997; 283(2): 419 - 425. [Abstract] [Full Text]
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G. Noll, R. R. Wenzel, S. de Marchi, S. Shaw, and T. F. Luscher Differential Effects of Captopril and Nitrates on Muscle Sympathetic Nerve Activity in Volunteers Circulation, May 6, 1997; 95(9): 2286 - 2292. [Abstract] [Full Text]
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G. Noll, R. R. Wenzel, M. Schneider, V. Oesch, C. Binggeli, S. Shaw, P. Weidmann, and T. F. Luscher Increased Activation of Sympathetic Nervous System and Endothelin by Mental Stress in Normotensive Offspring of Hypertensive Parents Circulation, March 1, 1996; 93(5): 866 - 869. [Abstract] [Full Text]
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