E Effects of Sildenafil on Exercise Capacity in Hypoxic Normal Subjects

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INTRODUCTION

E

XPOSURE TO HYPOXIAis associated with a decreased exercise capacity, which is explained by decreased O₂delivery to the tissues due to the combined effects of decreased max-

imum cardiac output and arterial oxygen content (CaO₂) (Fulco et al., 1998). At altitudes up to 4000 m, or equivalent hypoxia induced by a decreased fraction of inspired O₂ (F_I_O₂) from normal 0.21 to 0.12, maximum cardiac output is similar to that attained during normoxic ex-

© Mary Ann Liebert, Inc.

DOI: 10.1089/ham.2007.1058

Effects of Sildenafil on Exercise Capacity in Hypoxic Normal Subjects

VITALIE FAORO,¹ MICHEL LAMOTTE,² GAEL DEBOECK,¹ ADRIANA PAVELESCU,²SANDRINE HUEZ,² HERVÉ GUENARD,³

JEAN-BENOÎT MARTINOT,⁴ and ROBERT NAEIJE¹

ABSTRACT

Faoro, Vitalie, Michel Lamotte, Gael Deboeck, Adriana Pavelescu, Sandrine Huez, Hervé Gue- nard, Jean-Benoît Martinot, and Robert Naeije. Effects of sildenafil on exercise capacity in hypoxic normal subjects. High Alt. Med. Biol. 8:155–163, 2007.—The phosphodiesterase-5 inhibitor sildenafil has been reported to improve hypoxic exercise capacity, but the mechanisms ac- counting for this observation remain incompletely understood. Sixteen healthy subjects were in- cluded in a randomized, double-blind, placebo-controlled, cross-over study on the effects of 50-mg sildenafil on echocardiographic indexes of the pulmonary circulation and on cardiopulmonary cycle exercise in normoxia, in acute normobaric hypoxia (fraction of inspired O₂, 0.1), and then again after 2 weeks of acclimatization at 5000 m on Mount Chimborazo (Ecuador). In normoxia, sildenafil had no effect on maximum V_O₂ or O₂ saturation. In acute hypoxia, sildenafil increased maximum VO2from 275 to 326 mL/min/kg and O2saturation from 62%

6% to 68%9%. In chronic hypoxia, sildenafil did not affect maximum V_O₂ or O₂ saturation.

Resting mean pulmonary artery pressure increased from 163 mmHg in normoxia to 285 mmHg in normobaric hypoxia and 326 mmHg in hypobaric hypoxia. Sildenafil decreased pulmonary vascular resistance by 30% to 50% in these different conditions. We conclude that sildenafil increases exercise capacity in acute normobaric hypoxia and that this is explained by improved arterial oxygenation, rather than by a decrease in right ventricular afterload.

Key Words: pulmonary hypertension; altitude; hypoxic pulmonary vasoconstriction; pulmonary vascular resistance

1Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, Belgium.

2Department of Cardiology, Erasme University Hospital, Brussels, Belgium.

3Université de Bordeaux 2, Bordeaux, France.

4Department of Pneumology, St. Elisabeth Hospital, Namur, Belgium.

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ercise, and decreased V_O_2max is entirely explained by a decrease in O2delivery to the tissues due to a decrease in arterial O₂ content (CaO2) (Fulco et al., 1998; Calbet et al., 2003a).

More severe hypoxia is associated with a decreased maximum cardiac output and flow to exercising muscles, leading to a decrease in VO2max that is out of proportion to decreased CaO₂(Fulco et al., 1998; Calbet et al., 2003a). At altitudes up to about 5000 m, the decrease in arterial O₂ saturation (Sa_O₂) is compensated during acclimatization by an increase in he- moglobin content, so CaO₂remains unchanged or even increases compared to sea-level values, and decreased maximum exercise capacity then appears essentially determined by a decrease in maximum cardiac output (Fulco et al., 1998; Calbet et al., 2003b).

The reasons for a decrease in maximum cardiac output in hypoxia remain unclear (Rubin and Naeije, 2004). Possible explanations have been a decreased peripheral demand due to al- tered matching of diffusional and convectional O2 delivery processes (Wagner, 2000), a decrease in venous return together with a decreased chronotropic reserve (Reeves et al., 1987), or a decreased central nervous system output to the heart (Kayser, 2003). Hypoxia is associated with a parasympathetic nervous system-mediated decrease in maximum heart rate, but this has been shown to not explain the decreases in maximum cardiac output and V_O_2max(Boushel et al., 2001).

Most recently, the phosphodiesterase-5 inhibitor sildenafil has been shown to decrease pulmonary vascular resistance and increase V_O_2maxor maximum workload in hypoxic normal volunteers, suggesting that excessive right ventricular afterload due to hypoxic pulmonary vasoconstriction limits exercise capacity as a consequence of limited convectional O₂ transport to the exercising muscles (Ghofrani et al., 2004; Richalet et al., 2005). However, in these studies, sildenafil also increased arterial oxygenation, so that the relationship between sildenafil-induced pulmonary vasodilation and improved exercise capacity or workload could have been coincidental.

We therefore investigated the effects of sildenafil intake on exercise capacity as defined by a complete set of cardiopulmonary exercise

variables together with measurement of workload and arterial oxygenation, first in acute normobaric hypoxia and then after 2 weeks of acclimatization at 5000 m on Mount Chimborazo.

The results suggest that sildenafil may improve exercise capacity in hypoxic conditions owing to improved gas exchange, rather than to a hemodynamic effect.

METHODS

Subjects

Fourteen lowlanders, 6 women and 8 men, aged 24 to 56 yr, mean 36 yr, with a height of 1747 (meanSD) cm and a weight of 67 10 kg, gave a written informed consent to the study, which was approved by the Ethical Committee of the Erasme University Hospital.

All of them were healthy, with an unremark- able previous history and normal clinical examination, chest X-ray film, and electrocardio- gram.

Experimental design

Each subject underwent an echocardiographic examination in a semirecumbent posi- tion at rest and at a moderated level of exercise (pedaling without load), and an incremental cycle ergometer cardiopulmonary exercise test (CPET) at the FIO2 of 0.21 (breathing room air) or at the F_I_O₂ of 0.1 (from a premixed tank of O2 in nitrogen), and again after 10 days acclimatization at 3800 to 4800 m at the Whym- per hut (5000 m) on Mount Chimborazo (Ecuador). The hypoxic gas mixture was ad- ministered through masks, which tightly cov- ered the noses and mouths of the subjects during the entire investigation period. The masks were connected to a reservoir to accommodate for the ventilation-related changes in inspira- tory flow. The subjects were connected to the mask and gas mixture 30 min before the intake of sildenafil or placebo. The echocardiographic examinations and CPET were performed con- secutively, starting 30 min after the intake of sildenafil or a placebo according to a double- blind, randomized, placebo-controlled, cross- over design. The echocardiographic examination lasted on average 20 min. The dose of

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sildenafil was 50 mg. This dose and the timing of the measurements were selected on the ba- sis of previous experience in treating various forms of pulmonary hypertension and phar- macokinetic and pharmacodynamic data from studies on erectile dysfunction (Ghofrani et al., 2004; Guazzi et al., 2004, Galié et al., 2005). The sequence of FIO2 0.21 and 0.1 measurements at sea level was also randomized. Thus, at sea level every subject underwent a total of four sequences of echocardiographic examination and CPET, and at high altitude, two sequences of echocardiographic examination and CPET un- der either placebo or sildenafil in a random or- der, with each of these sequences always performed at least 24 h apart.

Clinical measurements

Systemic blood pressure was measured by sphygmomanometry, with mean pressure calculated as diastolic pressure 1/3 pulse pressure. A three-lead ECG was used to measure heart rate. Oxygen saturation (SO2) was measured by digit sensor pulse oximetry (Onyx 8500, Nonin Medical, Plymouth, MN, USA), which was tested and calibrated following the manufacturer’s recommendations. Particular attention was paid to quality of the signal, es- pecially during exercise, as it is known that accuracy and precision of pulse oximetry at exercise may be decreased by motion artifacts and decreased local perfusion (Yamaya et al., 2002).

Ambient temperature was between 20° and 25°C at sea level and in the Whymper hut (which was heated), and care was taken to start measurements only on warm and perfused fin- gers.

Echocardiography

Echocardiography was performed using a portable ultrasound system equipped with a 2.5-MHz probe (Cypress, Acuson/Siemens, Er- langen, Germany). Recordings were stored on optical disks and analyzed by two independent, blinded cardiologists experienced in echocardiography. Cardiac output (Q) was estimated from the left ventricular outflow tract cross-sectional area and continuous Doppler velocity-time integral measurements. Mean pulmonary artery pressure (Ppa) was calcu-

lated from the pulsed Doppler pulmonary artery flow acceleration time (Kitabatake et al., 1983). Systolic Ppa was estimated from the maximum velocity of tricuspid regurgitation (Yock and Popp, 1984). The intraobserver and interobserver variabilities for these measurements remained below 6%, with repeatability coefficients (Bland and Altman, 1999) of 14.4 msec for the acceleration time of pulmonary blood flow, 0.14 m/sec for the maximum velocity of the tricuspid regurgitant jets, and 0.25 L/min for cardiac output.

Cycle ergometer cardiopulmonary exercise test The CPET was performed in an upright po- sition on an electronically braked cycle ergometer (Monark, Ergomedic 818 E, Vansbro, Sweden) with breath-by-breath measurements, through a tightly fitted facial mask, of ventilation (VE), O2 uptake (VO2), and CO2 output (VCO2), using a fixed Cardiopulmonary Exer- cise System (Medisoft, Dinant, Belgium), calibrated with local barometric pressure indicated by the Ecuador Meteorological Institute. After 2 min at 0 W, the work rate was increased by 25 W/min. Peak VO2 was defined as the VO2

measured during the last 20 sec of peak exercise. Oxygen pulse was calculated by dividing VO2 by heart rate. The ventilatory equivalents for CO2(VE/VCO2) were calculated by dividing VEby VCO2. The anaerobic threshold was estimated by the V-slope method (Wasserman et al., 1999).

Statistics

Results are presented as meanSE. The sta- tistical analysis consisted of a two-way analysis of variance. When the F ratio of the analysis of variance reached a p0.05 critical value, paired Student’s t-tests were applied to com- pare specific situations (Winer et al., 1991). Cor- relations were calculated by linear regression analysis.

RESULTS

Hypoxic exposures were well tolerated, with mild degrees of headache, fatigue, weakness, lethargy, and, in one subject, some incoordina-

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tion and confusion. There was no noticeable side effect of sildenafil intake. Sufficient quality echocardiographic measurements could not be obtained in acute hypoxia in 1 subject. Ad- equate CPET measurements could not be obtained in acute hypoxia in 3 subjects.

Effects of hypoxia on hemodynamics and S_O2at rest (Table 1 and Figure 1)

Both acute and chronic hypoxia increased heart rate and cardiac output, while blood pressure slightly increased in chronic hypoxia only.

Hypoxia decreased resting SO2markedly more during acute than during chronic hypoxic exposure and increased mean and systolic Ppa more during chronic than acute hypoxic exposure. Hypoxia shifted mean Ppa versus cardiac output curves to higher pressures, and this hypoxia-associated pulmonary hypertension was more important in chronic than in acute hypoxia.

Effects of hypoxia on cardiopulmonary exercise test variables (Table 2)

Acute and chronic hypoxia decreased maximum workload, V_O2_max, V_O₂ at the anaerobic threshold, maximum heart rate, O2 pulse, and exercise S_O2 and increased V_E/V_CO₂ at the anaerobic threshold. Maximum ventilation de-

creased in acute hypoxia only, and maximum respiratory exchange ratio decreased in chronic hypoxia. Maximum ventilation, V_O_2max, V_O₂ at the anaerobic threshold, VE/VCO2, and O2pulse were slightly higher in chronic than in acute hypoxia, while maximum heart rate was lower.

Exercise S_O₂was lower in acute than in chronic hypoxia.

Effects of sildenafil in normoxia (Tables 1 and 2, Figure 1)

Sildenafil in normoxia increased cardiac output and heart rate, did not change blood pressure, mean or systolic Ppa, or SO2; decreased pulmonary vascular resistance (PVR) and decreased mean and systolic Ppa at the highest cardiac output. Sildenafil in normoxia did not affect any of the CPET variables.

Effects of sildenafil in acute hypoxia (Tables 1 and 2, Figure 1)

Sildenafil increased cardiac output and heart rate, did not change blood pressure and resting S_O₂, decreased PVR and systolic and mean Ppa, and shifted mean Ppa/Q curves to lower pressures by an average of 4 to 5 mmHg. Silde- nafil increased VO2max, O2 pulse, and exercise S_O₂, but did not affect maximum workload, maximum respiratory exchange ratio, ventila-

TABLE1. EFFECTS OFSILDENAFIL ONHEMODYNAMICS ANDOXYGENSATURATION INNORMOXIA, ACUTE

NORMOBARICHYPOXIA, ANDCHRONICHYPOBARICHYPOXIA INNORMAL SUBJECTS ATREST

Normoxia Acute hypoxia Chronic hypoxia

Variables Placebo Sildenafil Placebo Sildenafil Placebo Sildenafil

SO₂, % 98 1 98 1 65 3^c 66 3 81 1^c,i 80 1ⁱ

HR, beats/min 62 3 69 3^e 74 4^c 89 4^f 89 4^c,h 111 14^i,f

Psa, mmHg 91 2 88 1 90 2 87 2 97 2^b,h 94 2^h

Q, L/min 3.8 0.1 4.9 0.2^f 5.0 0.3^b 6.6 0.3^f 4.2 0.2^g 5.3 0.3^h,f

mPpa, mmHg 16 1 15 1 27 1^c 22 1^f 32 2^c,g 28 2^h,f

sPpa, mmHg 25 1 26 1 36 2^c 30 2^e 41 2^c,g 40 2ⁱ

PVR, WU 1.8 0.3 1.2 0.2^e 3.7 0.4^c 1.9 0.2^f 5.4 0.4^c,i 3.4 0.3^h,f SO₂, O2saturation; HR, heart rate; Psa, mean systemic arterial pressure; Q, cardiac output; Ppa, pulmonary artery pressure; m, mean; s, systolic; PVR, pulmonary vascular resistance; WU, Wood units, or mmHg/L/min.

The FIO2in normoxia and in hypoxia were 0.21 and 0.1, respectively, and the atmospheric pressure at 5000 m was 400 mmHg.

ap0.05.

bp0.01.

cp0.001, hypoxia compared with normoxia, without sildenafil.

dp0.05, ^ep0.01, ^fp0.001, sildenafil compared with placebo at the same inspired O2.

gp0.05, ^hp0.01, ⁱp0.001, chronic hypoxia compared with acute hypoxia.

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FIG. 1. Mean pulmonary artery pressure (mean Ppa) versus cardiac output (Q) plots in normoxia (N), in acute normobaric hypoxia (FIO20.1) (AH), and in chronic hypobaric hypoxia (CH), after intake of 50-mg sildenafil (S) (stippled lines) or a placebo (P) (straight lines). Cardiac output was increased by mild exercise. Vertical and horizontal bars represent standard error (SE). Hypoxia significantly shifted Ppa/Q relationships to higher pressures in chronic hypoxia more than in acute hypoxia. Sildenafil significantly shifted Ppa/Q relationships to lower pressures in all experimental conditions excepted in normoxia at baseline.

TABLE 2. EFFECTS OF HYPOXIA ANDSILDENAFIL ONCARDIOPULMONARY

EXERCISEVARIABLES INNORMALSUBJECTS ATSUBJECTS

Normoxia Acute hypoxia Chronic hypoxia

Placebo Sildenafil Placebo Sildenafil Placebo Sildenafil

Workload, W 270 20 265 22 179 18^c 175 15 180 15^c 182 15

VO_2max, mL/kg/min 45 3 46 3 25 2^c 28 2^d 31 2^c,g 33 2^g

VEmax, L/min 126 3 124 4 94 6^c 97 4 117 11^g 122 10^h

RER max 1.26 0.01 1.25 0.02 1.39 0.06^a 1.37 0.04 1.15 0.04^b 1.11 0.02

HR, beats/min 178 3 177 4 163 3^c 164 3 154 4^c,g 160 3^d

O2pulse, mL/beat 18 2 18 2 11 1^c 13 1^e 14 1^c,g 14 1

VO₂AT, mL/kg/min 29 3 29 3 16 1^c 17 3 21 2^b,i 23 2ⁱ

VE/VCO₂at AT 32 1 33 1 38 2^c 39 1 48 2^c,i 49 1ⁱ

Exercise SO₂, % 97 1 97 1 61 2^c 69 2^f 75 1^c,i 75 1ⁱ

Workload, maximum load; VO_2max, maximum O2uptake; VE, ventilation; RER, respiratory exchange ratio; HR, heart rate; AT, anaerobic threshold; VCO₂, CO2output; SO₂, oxygen saturation. The FIO2in normoxia and in hypoxia were 0.21 and 0.1, respectively, and the atmospheric pressure at 5000 m was 440 mmHg.

ap0.05, ^bp0.01, and ^cp0.001, hypoxia compared with normoxia.

dp0.05, ^ep0.01, and ^fp0.001, sildenafil compared with placebo.

gp0.05, ^hp0.01, and ⁱp0.001, chronic hypoxia compared with acute hypoxia.

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tion, heart rate, anaerobic threshold, and VE/VCO2at the anaerobic threshold.

Effects of sildenafil in chronic hypoxia (Tables 1 and 2, Figure 1)

Sildenafil increased cardiac output and heart rate, had no effect on blood pressure and resting SO2, decreased mean Ppa, not systolic Ppa, and shifted mean Ppa/Q curves to lower pressures by an average of 4 to 5 mmHg. Sildenafil did not affect any of the CPET variables and exercise S_O2.

Correlations

There were no correlations between Ppa, PVR, exercise S_O₂, and V_O_2max or maximum workload in normoxia, in acute hypoxia, or in chronic hypoxia respectively.

DISCUSSION

The present results suggest that sildenafil may improve hypoxic exercise capacity, but that this is more likely in acute than in chronic hypoxic conditions and is explained by an improvement in oxygenation, rather than by a pulmonary vasodilating effect.

Sildenafil is a phosphodiesterase-5 inhibitor approved for the treatment of erectile dysfunction (Carson, 1996), which has been reported to decrease PVR in normal subjects breathing hypoxic mixtures (Ghofrani et al., 2004; Zhao et al., 2001) or exposed to environ- mental hypoxia (Ghofrani et al., 2004; Richalet et al., 2005); in high altitude natives (Aldashev et al., 2005); in patients with lung fibrosis (Ghofrani et al., 2002); and in patients with left heart failure (Guazzi et al., 2004). Sildenafil has recently been shown in a randomized controlled trial to improve exercise capacity and pulmonary hemodynamics in patients with pulmonary arterial hypertension (Galie et al., 2005). In normoxic normal subjects at rest, 50 mg of sildenafil has been reported to be without any hemodynamic effect, with in particular no change in heart rate, cardiac output, blood pressure, or PVR (Guazzi et al., 2004). In the present study, the same dose of sildenafil at rest increased cardiac output, but did not af-

fect blood pressure or pulmonary artery pressure, suggesting systemic and pulmonary vasodilation. The pulmonary vasodilating effect of sildenafil in normoxia was confirmed when PVR was defined by Ppa measurements at exercise, which disclosed a shift of mean Ppa/Q lines to lower pressures, compatible with flow- independent decrease in pressure or resistance.

This observation is in keeping with hemodynamic studies in normal normoxic volunteers, which showed an increase in PVR after the administration of an ^L-arginine analogue to sup- press endogenous nitric oxide, suggesting a contribution of cGMP-mediated smooth mus- cle cell relaxation contributing to normally low pulmonary vascular tone (Stamler et al., 1994).

In the present study, acute hypoxic breathing with a FIO2of 0.1 increased mean Ppa by an average of 11 mmHg, with an increase in cardiac output by 1.2 L/min, which is in keeping with previous invasive hemodynamic studies in less severely hypoxic subjects breathing a F_I_O₂ of 0.11 or 0.12, who presented with an increase of mean Ppa by an average of 8 mmHg (Maggiorini et al., 2001; Zhao et al., 2001). This hypoxic pulmonary vasoconstriction, ex- pressed in hypoxia-induced increase in total PVR, was about half inhibited by sildenafil.

Partial inhibition of hypoxic pulmonary vasoconstriction by sildenafil has previously been reported in invasive or noninvasive studies in normal volunteers breathing a FIO2 of 0.10 (Ghofrani et al., 2004).

More chronic hypoxic exposure to 5000 m in our healthy volunteers further increased mean Ppa by 4 to 5 mmHg at the same cardiac output, indicating additional hypoxic vasoconstriction or remodeling. This is in keeping with previous invasive studies in normal volunteers studied in acute normobaric hypoxic conditions and the day after arrival at an altitude of 4559 m (Maggiorini et al., 2001). In a recent study on normal volunteers, the median of systolic Ppa was lower at 5000 m at Mount Ever- est Base Camp than during acute hypoxic breathing, but this discrepancy might be explained by expression of the results as median values (Ghofrani et al., 2004). In the present study, sildenafil in chronic hypobaric hypoxia inhibited PVR to a similar extent as in acute hypoxia, as in previous studies on normal volun-

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teers at an altitude of 5000 m (Ghofrani et al., 2004). More chronic administration of sildenafil at a dose of 50 mg tid in normal subjects during a 1-week stay at 4350 m may be more ef- fective in inhibiting hypoxia-induced increase in mean Ppa or resistance, as evidenced by a tendency to normalization of the acceleration time of pulmonary blood flow (Richalet et al., 2005).

In the present study, the acute intake of sildenafil was associated with an improvement in SO2 during exercise in acute normobaric hypoxia, but not in chronic hypobaric hypoxia.

This result is strikingly similar to that previously reported after acute intake of 50-mg sildenafil in normal volunteers exercising in acute normobaric hypoxia and then again at 5000 m (Ghofrani et al., 2004). More chronic intake of sildenafil 50 mg tid is associated with a persis- tent increase in SO2and PaO2at rest and at exercise (Richalet et al., 2005). In the latter study, sildenafil decreased the alveolar to arterial PO2

gradient, suggesting an improvement in pulmonary gas exchange. Similar effects have been reported in patients with lung fibrosis (Ghofrani et al., 2002) or chronic heart failure (Guazzi et al., 2004). Possible explanations for this intriguing finding are an improvement in mixed venous oxygenation (Dantzker, 1983), an improvement in ventilation–perfusion relationships because of preferential vasodilation in the most aerated lung regions (Ghofrani et al., 2002), or an improved diffusion capacity (Guazzi et al., 2004). In chronic heart failure, sildenafil was found to improve the membrane rather than the capillary blood volume compo- nent of the diffusion capacity for carbon monoxide, which is compatible with a decrease in interstitial edema, even though, in that study, pulmonary artery wedge pressure remained unchanged (Guazzi et al., 2004).

Oxygen saturations were measured using digital sensor pulse oximetry. The accuracy and precision of pulse oximeters has been shown to decrease in hypoxia and at exercise (Yamaya et al., 2002). The use of finger sensors may decrease signal quality owing to motion artifacts and decreased local perfusion (Ya- maya et al., 2002). In the present study, particular attention was paid to signal quality at exercise, with the test finger prevented from

gripping the handlebar. The observed changes in SO2in hypoxia and during hypoxic exercise agreed with those previously reported in similar experimental conditions (Ghofrani et al., 2004). In addition, because of the cross-over design of the study, it seems reasonable to assume that the increase in noise to signal ratio related to insufficient or variable accuracy and precision would have been distributed equally to the placebo and sildenafil treatments.

In the present study, exercise capacity was decreased in hypoxia, as expected, to about 60% of baseline normoxic value (Fulco et al., 1998). It is important to note that both VO2max

and V_O₂at anaerobic threshold were increased in chronic compared to acute hypoxia, in spite of higher Ppa and PVR. This is likely related to markedly higher SO2 and is in keeping with a previous study on normal volunteers and with similar experimental design, but with assess- ment of exercise capacity only by a measure of maximum workload (Ghofrani et al., 2004).

Sildenafil improved V_O_2max only in acute hypoxia, not in chronic hypoxia, in spite of a pro- portionally more important pulmonary vasodilating effect in chronic hypoxia, and this appeared clearly related to the improved S_O₂ observed in acute hypoxic conditions as well.

An additional argument against sildenafil-induced pulmonary vasodilation as a cause of increased hypoxic V_O_2max may be that sildenafil did not affect the ventilatory equivalent for CO₂

at the anaerobic threshold, which normally decreases with improved VO2max in patients with pulmonary hypertension responding to va- sodilator therapy (Wensel et al., 2000). It is to be noted that sildenafil in acute hypoxia did not affect workload, which underscores that a measurement of V_O_2max is more sensitive than workload to assess maximum aerobic exercise capacity (Wasserman et al., 1999). The predic- tion of VO2max from workload is known to be inaccurate due to ergometer calibration un- certainties and variable intersubject VO2kinet- ics at a given incremental workload regimen (Wasserman et al., 1999).

The maximum respiratory exchange rate (RER) was higher in acute hypoxia and lower in chronic hypoxia. This has been previously reported and shown to be essentially related to changes in lactate and glucose metabolism,

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which may themselves be at least partly explained by sympathetic adrenergic responses (Brooks et al., 1991). Blood lactate in acclima- tized subjects at maximal exercise decreases with increasing altitude (Sutton et al., 1994).

The mechanisms of this lactate paradox, which accounts for lower maximum RER after acclimatization to high altitudes, remain incompletely understood.

CONCLUSION

In summary, sildenafil may limit to a certain extent the decrease in aerobic exercise capacity normally seen in hypoxic conditions, but this is likely related to an increased O₂ delivery to the exercising muscles owing to an increase in arterial O₂ content, rather than to a hemodynamic effect.

ACKNOWLEDGMENTS

The authors thank Medisoft, Inc., Dinant, Belgium, for providing the cardiopulmonary exercise equipment, and Siemens, Erlangen, Germany, for providing the portable echocardiographic device.

The authors also thank M. Martinot, from Medisoft, Inc., for his tireless help in solving the technical problems of hypoxic gas exchange measurements and Marie-Thérèse Gautier and Olivier Xhaet, from the Department of Cardi- ology of the Erasme University Hospital Brus- sels, for expert assistance in the experiments.

Sildenafil (Viagra^®) was a gift from Pfizer Inc., Sandwich, UK.

REFERENCES

Aldashev A.A., Kojonazarov B.K., Amatov T.A., Sooron- baev T.M., Mirrakhimov M.M., Morrell N.W., Wharton J., and Wilkins M.R. (2005). Phosphodiesterase type 5 and high altitude pulmonary hypertension. Thorax.

60:683–687.

Bland J., and Altman D. (1999). Measuring agreement in method comparison studies. Stat. Methods Med. Res.

8:135–160.

Boushel R., Calbet J.A., Radegran G., Sondergaard H., Wagner P.D., and Saltin B. (2001). Parasympathetic

neural activity accounts for the lowering of exercise heart rate at high altitude. Circulation. 104:1785–1791 Brooks G. A., Butterfield G. E., Wolfe R. R., Groves B. M., Mazzeo R. S., Sutton J. R., Wolfel E. E., and Reeves J.

T. (1991). Decreased reliance on lactate during exercise after acclimatization to 4,300 m. J. Appl. Physiol.

71:333–341.

Calbet J.A., Boushel R., Radegran G., Sondergaard H., Wagner P.D., and Saltin B. (2003a). Determinants of maximal oxygen uptake in severe acute hypoxia. Am.

J. Physiol. Regul. Integr. Comp. Physiol. 284:R291–

R303.

Calbet J.A., Boushel R., Radegran G., Sondergaard H., Wagner P.D., and Saltin B. (2003b). Why is VO2 max after altitude acclimatization still reduced despite normalization of arterial O2 content? Am. J. Physiol. Regul.

Integr. Comp. Physiol. 284:R304–R316.

Carson, C.C., 3rd. (1996). Sildenafil: a 4-year update in the treatment of 20 million erectile dysfunction patients.

Curr. Urol. Rep. 4:488.

Dantzker D.R. (1983). The influence of cardiovascular function on gas exchange. Clin. Chest Med. 4:149–159.

Fulco C.S., Rock P.B., and Cymerman A. (1998). Maximal and submaximal exercise performance at altitude.

Aviat. Space Environ. Med. 69:793–801.

Galie N., Ghofrani H.A., Torbicki A., Barst R.J., Rubin L.J., Badesch D., Fleming T., Parpia T., Burgess G., Branzi A., Grimminger F., Kurzyna M., and Simonneau G.

(2005). Sildenafil use in pulmonary arterial hypertension (SUPER) study group. Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med.

353:2148–2157.

Ghofrani H. A., Reichenberger F., Kohstall M. G., Mrosek E. H., Seeger T., Olschewski H., Seeger W., and Grim- minger F. (2004). Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest Base Camp. Ann. Intern. Med. 141:169–177.

Ghofrani H.A., Wiedemann R., Rose F., Schermuly R.T., Olschewski H., Weissmann N., Gunther A., Walmrath D., Seeger W., and Grimminger F. (2002). Sildenafil for treatment of lung fibrosis and pulmonary hypertension:

a randomised controlled trial. Lancet. 360:895–900.

Guazzi M., Tumminello G., Di Marco F., Fiorentini C., and Guazzi M.D. (2004). 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. 44:2339–2348.

Kayser B. (2003). Exercise starts and ends in the brain.

Eur. J. Appl. Physiol. 90:411–419.

Kitabatake A., Inoue M., Asao M., Masuyama T., Tanouchi J., Morita T., Mishima M., Uematsu M., Shi- mazu T., Hori M., and Abe H. (1983). Noninvasive eval- uation of pulmonary hypertension by a pulsed Doppler technique. Circulation. 68:302–309.

Maggiorini M., Melot C., Pierre S., Pfeiffer F., Greve I., Sartori C., Lepori M., Hauser M., Scherrer U., and Naeije R. (2001). High-altitude pulmonary edema is ini- tially caused by an increase in capillary pressure. Cir- culation. 103:2078–2083.

(9)

Reeves J.T., Groves B.M., Sutton J.R., Wagner P.D., Cymerman A., Malconian M.K., Rock P.B., Young P.M., and Houston C.S. (1987). Operation Everest II: preser- vation of cardiac function at extreme altitude. J. Appl.

Physiol. 63:531–539.

Richalet J.P., Gratadour P., Robach P., Pham I., Dechaux M., Joncquirt-Latarjet A., Mollard P., Brugniaux J., and Cornolo J. (2005). Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am. J.

Respir. Crit. Care. Med. 171:275–281.

Rubin L.J., and Naeije R. (2004). Sildenafil for enhanced performance at high altitude? Ann. Intern. Med. 141:

233–235.

Stamler J.S., Loh E., Roddy M.A., Currie M.A., and Crea- ger M.A. (1994). Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans.

Circulation. 89:2035–2040.

Sutton J.R., Reeves J.T., Wagner P.D., Groves B.M., Cymerman A., Malconian M.K., Rock P.B., Young P.M., Walter S.D., and Houston C.S. (1994). Operation Ever- est II: oxygen transport during exercise at extreme sim- ulated altitude. J. Appl. Physiol. 64:1309–1321.

Wagner P.D. (2000). Reduced maximal cardiac output at altitude—mechanisms and significance. Respir. Phys- iol. 120:1–11.

Wasserman K., Hansen J.E., Sue D.Y., and Whipp B.J.

(1999). Principles of Exercise Testing and Interpretation, 3rd ed. Lippincott Williams & Wilkins, Baltimore; pp.

143–164.

Wensel R., Opitz C.F., Ewert R., Bruch L., and Kleber F.X.

(2000). Effects of iloprost inhalation on exercise capac-

ity and ventilatory efficiency in patients with primary pulmonary hypertension. Circulation. 101:2388–2392.

Winer B.J., Brown D.R., and Michels K.M. (1991). Statis- tical principles in experimental design, 3rd ed. Mc- Graw-Hill, New York; pp. 220–283.

Yamaya Y., Boogard H.J., Wagner P.D., Niizerki K., and Hopkins S.R. (2002). Validity of pulse oximetry during maximal exercise in normoxia, hypoxia, and hyperoxia.

J. Appl. Physiol. 92:162–168.

Yock P.G., and Popp R.L. (1984). Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circu- lation. 70:657-662.

Zhao L., Mason N.A., Morrell N.W., Kojonazarov B., Sadykov A., Maripov A., Mirrakhimov M.M., Aldashev A., and Wilkins M.R. (2001). Sildenafil inhibits hypoxia- induced pulmonary hypertension. Circulation. 104:

424–428.

Address reprint requests to:

Robert Naeije, MD Department of Physiology, Erasme

Campus CP 604 808 Lennik Road B-1070 Brussels, BELGIUM E-mail: rnaeije@ulb.ac.be Received October 25, 2006; accepted in final form February 16, 2007.