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Influence of inhaled nitric oxide on gas exchange duringnormoxic and hypoxic exercise in highly trained cyclists

A. WILLIAM SHEEL, MICHAEL R. EDWARDS,

GARTH S. HUNTE, AND DONALD C. MCKENZIE Allan McGavin Sports Medicine Center and School of Human Kinetics, The Universityof British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

Received 10 December 1999; accepted in final form 13 September 2000

Sheel, A. William, Michael R. Edwards, Garth S.Hunte, and Donald C. McKenzie. Influence of inhalednitric oxide on gas exchange during normoxic and hypoxicexercise in highly trained cyclists. J Appl Physiol 90:926932, 2001.This study tested the effects of inhalednitric oxide [NO; 20 parts per million (ppm)] during normoxicand hypoxic (fraction of inspired O2 14%) exercise on gasexchange in athletes with exercise-induced hypoxemia.

Trained male cyclists (n 7) performed two cycle tests toexhaustion to determine maximal O2 consumption (VO2 max)and arterial oxyhemoglobin saturation (SaO2, Ohmeda Bioxear oximeter) under normoxic (VO2 max 4.88 0.43 l/minand SaO2 90.2 0.9, means SD) and hypoxic (VO2 max 4.24 0.49 l/min and SaO2 75.5 4.5) conditions. On athird occasion, subjects performed four 5-min cycle tests,each separated by 1 h at their respective VO2 max, underrandomly assigned conditions: normoxia (N), normoxia NO(N/NO), hypoxia (H), and hypoxia NO (H/NO). Gas ex-change, heart rate, and metabolic parameters were deter-mined during each condition. Arterial blood was drawn atrest and at each minute of the 5-min test. Arterial P O2 (PaO2),arterial PCO2, and SaO2 were determined, and the alveolar-arterial difference for PO2 (A-aDO2) was calculated. Measure-

ments of PaO2 and SaO2 were significantly lower and A-aDO2was widened during exercise compared with rest for allconditions (P 0.05). No significant differences were de-tected between N and N/NO or between H and H/NO for PaO2,SaO2 and A-aDO2 (P 0.05). We conclude that inhalation of20 ppm NO during normoxic and hypoxic exercise has noeffect on gas exchange in highly trained cyclists.

exercise-induced hypoxemia; pulmonary edema; ventilation-perfusion inequality; diffusion disequilibrium

SOME HIGHLY TRAINED MALE ENDURANCE athletes experi-ence decreases in arterial PO2 (PaO

2) and arterial oxy-

hemoglobin saturation (SaO2) and a widened alveolar-

arterial difference for O2 (A-aDO2) during heavyexercise (5, 13). The cause and significance of exercise-induced arterial hypoxemia (EIH) has been the topic ofa considerable research effort; however, the mecha-nism(s) responsible remains controversial. Four poten-tial factors have been identified: 1) venoarterial shunt,2) relative alveolar hypoventilation, 3) ventilation-per-

fusion (VA/Q) inequality, and 4) diffusion limitation Venoarterial shunt has been identified as a minocontributor, and relative alveolar hypoventilation hasa controversial role in the pathophysiology of EIH (6)VA/Q relationships have been shown to worsen withexercise (10), and, during maximal exercise, 60% othe widened A-aDO2 can be explained by VA/Q mismatch (14). Pulmonary interstitial edema may explainboth VA/Q inequality and diffusion limitations (11, 26)This would be expected to negatively influence gasexchange in the lung by lowering the compliance of thealveoli and by compressing small blood vessels, resulting in nonuniform airflow and blood flow distributionin the lungs (11). However, present techniques havefailed to provide precise quantification of extravascularlung water or identification of the specific mechanismsresponsible for the development of interstitial edema(6).

Inhaled nitric oxide (NO) is a potent and selectivepulmonary vasodilator (8, 9). Inhalation of NO habeen used effectively to treat several respiratory disor

ders in humans (1, 15, 16) but has been shown to bedetrimental in chronic obstructive pulmonary disease(1). The positive effects of NO are explained by apreferential distribution of inhaled NO to well-ventilated alveolar units, a reduction in the dispersion oventilation distribution, lowering of pulmonary vascular pressures, and improved gas exchange. Inhalationof NO has also been utilized to exert a beneficial effecton arterial oxygenation in mountaineers with highaltitude pulmonary edema (27). Although the mechanisms of EIH remain debatable, there is some indirectevidence to support the development of transient interstitial edema as a mechanism for a widened A-aDO2 (323). We sought to test the hypothesis that inhaled NO

would improve oxygenation during exercise in athleteswith EIH by reducing A-aDO2.

METHODS

Subjects. Highly trained male cyclists were recruited toparticipate in this study (n 8). One subject was forced towithdraw due to difficulties with placement of the arteria

Address for reprint requests and other correspondence: D. C.McKenzie, Allan McGavin Sports Medicine Center, 3055 WesbrookMall, Vancouver, BC, Canada V6T 1Z3 (E-mail: [email protected]).

The costs of publication of this article were defrayed in part by thepayment of page charges. The article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734solely to indicate this fact.

J Appl Physiol90: 926932, 2001.

8750-7587/01 $5.00 Copyright 2001 the American Physiological Society http://www.jap.or926


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catheter; therefore, all data are reported for n 7. Thisinvestigation was divided into two parts. Subjects who metthe inclusion criteria in part 1 participated in part 2. Inclu-sion criteria were 1) normal spirometry, that is, no history ofasthma or cardiorespiratory disease, 2) maximal O2 con-sumption (VO2 max) 60 ml kg

1min1 and/or 5 l/min, 3)

development of EIH (maximal exercise SaO2 91.0%), and 4)between the ages of 18 and 40 yr. Before testing was started,subjects received a verbal description of the experiment andcompleted a written, informed consent form. This study wasapproved by the Clinical Screening Committee for Researchand Other Studies Involving Human Subjects of the Univer-

sity of British Columbia. Preliminary screening: part 1. Subjects reported to the

Applied Physiology Laboratory in the Allan McGavin SportsMedicine Center (Univ. British Columbia), having refrainedfrom exhaustive exercise for 24 h, abstained from ingestion offood or fluid for 4 h, except for water, and abstained fromalcohol and caffeine for 12 h. Subjects weight and heightwere measured and recorded. Both spirometry and pulmo-nary diffusion measurements for carbon monoxide (DLCO)were collected using the same commercial apparatus (CollinsDS/PLUS II, Braintree, MA). DLCO was determined using thesingle-breath method. Before DLCO and spirometry measure-ments were made, subjects sat and rested for 30 min toensure a resting heart rate and pulmonary capillary blood

volume.

VO2 max was determined using an incremental test to ex-haustion on an electronically braked cycle ergometer (Quin-ton Excalibur, Lode, Groningen, The Netherlands). Subjectspedaled at a self-chosen cadence at a progressing workload,which started at 0 W and increased 30 W/min. Subjectsinspired through an air flowmeter (Vacumetrics model17150, Ventura, CA) using a two-way nonrebreathing valve(Hans-Rudolph, model 2700B, Kansas City, KS). Expired airpassed into a 5-liter mixing chamber from which gas sampleswere analyzed at a rate of 300 ml/min for O2 and CO2 (S-3AO2 analyzer and CD-3A CO2 analyzer, Applied Electrochem-istry, Pittsburgh, PA). Expired gases and minute ventilation(VE) were recorded using a computerized system (Rayfield,Waitsfield, VT). Gas analyzers were calibrated with gases ofknown concentration, and the air flowmeter was calibrated

by passing 100 liters of air through the system. Heart ratewas recorded every 15 s using a portable heart rate monitor(Polar Vantage XL, Kempele, Finland). SaO2 was measuredby a pulse oximeter (Ohmeda Biox 3740, Louisville, CO), with

values averaged and recorded every 5 s using a personalcomputer. Before placement of the oximeter sensor to thepinna of the ear, a topical vasodilator cream (Finalgon,Boehringer/Ingeheim, Burlington, ON) was applied to in-crease local perfusion. Attainment of VO2 max was consideredwhen at least three of the following four were observed: 1) aplateau in O2 consumption (VO2) with increasing workload,2)respiratory exchange ratio (RER) 1.15, 3) attainment of90% of age predicted maximal heart rate, and/or 4) volitional

fatigue. During part 1, cycle ergometry subjects inspiredcompressed air [fraction of inspired O2 (FIO2) 20.93%]. Theair was delivered from a large cylinder through a closedcontainer of water for humidification and then into a largemeteorological balloon, which acted as a reservoir for inspired air. Those who met the inclusion criteria returned ona separate day at least 72 h later to perform another maximacycle ergometry test under hypoxic conditions (FIO2 14.00%). This FIO2 has previously been used to accentuatedecreases in SaO2 in exercising trained men (17). Expiredgases, heart rate, and SaO2 were determined during thehypoxic exercise session as described for the normoxic condi

tions.Inhaled NO: part 2. After completion of both VO2 max tests

(normoxic and hypoxic), subjects who met the inclusion criteria returned on a separate day at least 72 h later. A timeline describing the experimental protocol is shown in Fig. 1Subjects were randomly assigned and blinded to each of thefour following conditions: 1) normoxia (N), 2) normoxia NO(N/NO), 3) hypoxia (H), and 4) hypoxia NO (H/NO). Participants performed a 10- to 15-min cycling warm-up at aself-selected workload and then sat quietly on the cycleergometer for 5 min, at which point resting data were obtained. Cycling intensity was then manually increased over 1min to 100% of their respective maximum normoxic or hypoxic workload as determined in part 1. Subjects cycled athis intensity for 5 min, and cardiorespiratory variables were

recorded at each minute in the same fashion as for part 1Arterial blood samples were drawn at rest and at each min ofthe 5-min test. After each test condition, subjects cycledeasily (3050 W) for 10 min and then rested for 50 min beforecommencing the next test condition. A physician was inattendance at all times and was responsible for the safety othe subjects during the study.

Table 1. Descriptive and resting pulmonaryfunction data

Age, yr 28.9 3.9Height, cm 181.4 7.5Mass, kg 74.7 6.6FVC, liters 5.59 0.81 (102 14

FEV1, liters 4.58 0.73 (102 15FEF2575%, l/s 4.52 0.91 (102 18FEV1 /FVC, % 80.54 5.82 (98 7)FEFmax, l/s 9.95 1.08 (102 17DLCO, ml min

1Torr1 36.99 5.04* (117 19

VA, liters 5.26 1.42DLCO/VA 7.33 1.65

Values are means SD. Actual values are shown, with %predictedin parentheses. FVC, forced vital capacity; FEV1, forced expiredvolume in 1 s; FEF2575%, forced expiratory flow at 2575% of FVCFEFmax, maximal forced expiratory flow rate; DLCO, pulmonary diffusion capacity for CO; VA, alveolar volume; DLCO/VA, pulmonarydiffusion capacity for CO/VA. *Significantly different from predicted(P 0.05).

Fig. 1. Overview of experimental protocol, repeated for each gas mixture condition of normoxia (N), normoxia 20parts per million (ppm) nitric oxide (N/NO), hypoxia (H), and hypoxia 20 ppm nitric oxide (H/NO). S, sample forblood and cardiorespiratory variables taken after breathing test gas mixture at rest for 5 min and during each

minute of 5-min maximal cycling; VO2max, maximal O2 consumption.

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During N, subjects rested for 5 min and cycled whilebreathing normoxic gas. Condition N/NO consisted of nor-moxic gas with 20 parts per million (ppm) NO delivered to theinspiratory tubing. During condition H, subjects rested for 5min and cycled while inhaling hypoxic gas (FIO2 14.00%);condition H/NO consisted of the same hypoxic gas with 20ppm NO. During all conditions, the inspired air was deliv-ered from a large cylinder through water for humidificationand then into a large meteorological balloon, which acted asa reservoir before being inspired by the subject. NO wasdelivered at the distal end of the tubing while inspiredconcentrations of O2, NO, and nitrogen dioxide were moni-tored continuously during each test condition 5 cm from thesubjects mouth using a commercial apparatus (PulmoNOxII, Pulmonox, Tofield, AB). The NO-delivery system wascalibrated before each experiment as per the manufacturersspecifications. The concentration of NO used in the presentstudy (20 ppm) has previously been shown to improve VA/Qdistributions, PaO2, and pulmonary vascular resistance inpigs (24), reverse hypoxic pulmonary vasoconstriction (HPV),and redistribute blood flow to better ventilated areas of thelung in sheep (21).

Arterial blood sampling. A 20-gauge arterial catheter wasinserted in the radial artery of the nondominant hand bypercutaneous cannulation using 1% local anesthesia (lido-

caine) and sterile technique and was then secured to the skinAdequate collateral circulation via the ulnar artery (Allentest) was estimated before the cannula was inserted. A minimum volume extension tube, connected in series with twothree-way stopcocks arranged at right angles, was flushedwith a saline-heparin solution. A rapid response ( 0.01 sthermistor (18T, Physitemp Instruments, Clifton, NJ) usedto measure peak arterial blood temperature was insertedthrough a Touhy-Borsch heparin lock (Abbott Hospitals

North Chicago, IL). Catheter patency was maintained with acontinuous heparin infusion (1 ml 1:1,000 units in 500 mnormal saline at 3 ml/h). At the onset of sampling, 12 ml ofblood was withdrawn, and the final 3 ml was collected inpreheparinized plastic syringes. The remaining 9 ml werethen slowly reinfused. Samples were withdrawn at rest andat 1-min intervals for the duration of each test (4 conditions 6 samples per condition 24 samples/subject). Bloodsamples were placed on ice until analyzed for H concentration, PO2, PCO2, base excess, and HCO3

(CIBA-Corning 278blood-gas system, CIBA-Corning Diagnostics, Medfield, MA)PaO2 was corrected for temperature and H

concentrationTemperature increased 0.9 0.1C (mean SD) from rest to5 min of exercise across all trials. SaO2 levels were calculatedbased on corrected PaO2. The alveolar gas equation was used

to calculated alveolar PO2 and A-aDO2 (20). Statistical analyses. Mean values and measures of vari

ability were determined for descriptive, anthropometric, andlung function variables obtained during preliminary screening. Maximal cycle ergometry data from part 1 were compared using t-tests for dependent samples (normoxia vshypoxia). Experimental data were analyzed using a four(condition) by six (time) two-way factorial ANOVA with repeated measures on both factors. When sphericity was noassumed, Greenhouse-Geisser P values were utilized. Whensignificant Fratios were observed, Scheffes test was appliedpost hoc to determine where the differences occurred. Thelevel of significance was set at P 0.05. Statistical powercalculations were performed a priori to estimate an appropriate minimum sample size of five. A sample size of seven

was utilized to ensure sufficient statistical power (1 0.8).

RESULTS

Physical and maximal exercise data. Descriptive dataand resting pulmonary function data are presented in

Table 2. Maximal exercise values during maximalcycle ergometer tests

Normoxia(FIO2 20.93%)

Hypoxia(FIO2 14.00%)

VO2max, l/min 4.88 0.43 4.24 0.49*VO2max,

ml kg1 min1 65.3 1.6 56.6 5.6*VEmax, l/min 175.9 10.2 168.2 11.5

RER, VCO2/VO2 1.20 0.02 1.12 0.07*HRmax, beats/min 188 4 179 3*Resting SaO2, % 97.7 0.6 97.0 0.8Lowest SaO2, % 90.2 0.9 75.5 4.5*Power, W 449 39 371 38*

Values are means SD. FIO2, fraction of inspired O2; VO2max,maximal O2 consumption; VEmax, maximal minute ventilation; RER,respiratory exchange ratio; VCO2, CO2 production; VO2, O2 consump-tion; HRmax, maximal heart rate; SaO2, arterial oxyhemoglobin sat-uration. * Significantly different from normoxia (P 0.05). Signif-icantly different from resting SaO2 (P 0.05).

Table 3. Ventilatory and performance parameters during normoxic and normoxic NO 5-min cycle ergometry

Normoxia Normoxia NO

Rest

Minute

Rest

Minute

1 2 3 4 5 1 2 3 4 5

VO2, l/min 0.44 0.21

3.70 0.58*

4.30 0.59*

4.37 0.68*

4.37 0.77*

4.42 0.81*

0.70 0.26

3.93 0.85*

4.29 0.81*

4.69 0.61*

4.82 0.69*

4.95 0.62*

VO2,ml kg1 min1

7.64 3.08

53.04 9.23*

58.67 9.14*

60.05 9.54*

59.33 10.44*

60.21 11.17*

10.81 2.37

55.58 11.39*

60.77 12.12*

64.70 10.27*

67.42 11.09*

69.37 9.77*

VE, l/min 16.07 4.98

120.27 29.20*

150.08 8.73*

156.93 12.98*

157.68 14.59*

160.01 15.23*

14.07 4.77

119.39 23.51*

146.22 11.21*

155.30 12.21*

157.86 13.37*

160.21 16.07*

RER 0.87 0.16

0.93 0.21

1.06 0.18*

1.06 0.18*

1.06 0.18*

1.03 0.16*

0.84 0.04

0.88 0.03

1.00 0.06*

1.02 0.09*

0.99 0.11*

0.98 0.11*

HR, beats/min 89 17

167 6*

174 3*

177 3*

179 4*

180 6*

93 13*

165 3*

173 5*

177 6*

179 6*

181 5*

Power, W 0 390 36.1*

368 32.5*

353 44.6*

336 61.7*

333 60.9*

0 378 44.8*

355 59.0*

341 66.2*

330 49.0*

330 67.2*

Values are means SD. NO, nitric oxide; VE, minute ventilation; HR, heart rate. *Significantly different from rest (P 0.05).

928 INHALED NO DURING EXERCISE


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Table 1. Lung parameters were within normal valuespredicted for men of similar age, height, and weightexcept for DLCO, which was significantly elevated. Data

from normoxic and hypoxic maximal cycle ergometrytests are presented in Table 2. Significant differenceswere observed between normoxic and hypoxic conditionsfor VO2 max, RER, maximal heart rate, and power output,whereas no significant differences were detected for VE.From rest to maximal exercise, mean values for SaO

2

dropped significantly under both normoxic (97.7 to 90.2)and hypoxic (97.0 to 75.5) conditions.

Metabolic and power output during 5-min cycling.Metabolic and power output data are shown in Tables3 and 4. No significant differences were detected be-tween N and N/NO or between H and H/NO for V O2,VE, RER, heart rate, or power output.

Arterial blood variables during 5-min cycling. Alldata are reported in Tables 5 and 6 and Figs. 2 and 3.Across all time points, there were no significant differ-ences for PaO

2

between N and N/NO or between H andH/NO (see Fig. 2). Both hypoxic conditions were signifi-

cantly lower than both normoxic conditions at all mea-surement periods. PaO

2

values were significantly lower a1, 2, 3, 4, and 5 min of exercise compared with rest for all

inspired gas conditions. Similar results were observed forSaO2, except that values at 1 and 2 min were not signifi-cantly different from rest under conditions of N andN/NO (see Fig. 3). A-aDO2 was significantly different atall time periods compared with rest for all inspired gasmixtures, and significant differences were detected between N/NO and H at rest and during all exercise measurements. Arterial PCO2 (PaCO2) was not significantlydifferent between gas conditions but was lower comparedwith rest throughout all exercise for H and H/NO and atminutes 3, 4, and 5 for both N and N/NO. No statisticallysignificant differences were detected between N vs. N/NOor between H vs. H/NO for pH, HCO3

, or base excess(Tables 5 and 6).

DISCUSSION

The present study is the first to systematically examine the effects of inhaled NO during normoxic and

Table 4. Ventilatory and performance parameters during hypoxic and hypoxic NO 5-min cycle ergometry

Hypoxia Hypoxia NO

Rest

Minute

Rest

Minute

1 2 3 4 5 1 2 3 4 5

VO2, l/min 0.52 0.22

3.31 0.42*

3.60 0.50*

3.76 0.56*

3.86 0.64*

4.03 0.61*

0.48 0.20

3.72 0.56*

3.98 0.56*

4.19 0.45*

4.13 0.52*

4.17 0.44*

VO2,

ml kg1 min16.53

2.55

45.48 6.42*

50.13 6.21*

53.05 3.06*

53.96 3.69*

55.98 2.68*

5.50 1.34

49.83 7.03*

54.06 6.60*

56.38 4.40*

55.77 5.37*

55.93 5.51*

VE, l/min 14.10 4.15

126.62 16.44*

138.62 8.74*

147.24 17.74*

156.02 22.94*

157.51 20.52*

21.22 9.29

134.21 17.48*

149.78 26.20*

153.71 23.33*

153.65 24.10*

155.63 21.76*

RER 0.94 0.12

1.04 0.11*

1.12 0.04*

1.09 0.04*

1.08 0.07*

1.06 0.08*

0.95 0.11

1.01 0.06*

1.07 0.09*

1.05 0.08*

1.02 0.09*

0.99 0.09*

HR, beats/min 89 14

166 4*

171 4*

174 2*

176 3*

177 3*

92 18

166 6*

171 5*

173 6*

175 6*

177 6*

Power, W 0 326.3 33.4*

303.9 40.7*

296.4 55.4*

288.6 55.0*

284.3 52.3*

0 329.3 30.3*

307.0 42.7*

278.6 29.3*

263.3 30.8*

262.6 35.6*

Values are means SD. *Significantly different from rest (P 0.05).

Table 5. Blood variables during normoxic and normoxic NO 5-min cycle ergometry

Normoxia Normoxia NO

Rest

Minute

Rest

Minute

1 2 3 4 5 1 2 3 4 5

PaO2, Torr 103.8 8.2

93.2 4.7*

89.4 6.7*

85.0 7.2*

85.6 8.8*

84.2 9.3*

98.7 5.2

85.7 8.9*

81.6 8.1*

78.8 8.2*

78.7 9.7*

78.0 10.2*

SaO2, % 98.0 0.7 97.4 0.4 96.3 0.4 95.2 0.7* 94.7 1.3* 94.0 1.8* 97.7 0.3 96.6 0.6 95.2 1.3 94.3 1.2* 93.7 1.0* 93.4 1.0*PaCO2, Torr 38.8

3.138.2

2.437.2

3.136.2

3.1*33.8

3.8*31.2

5.5*37.2

4.636.5

4.737.0

4.335.4

3.9*34.3

3.7*32.3

3.6*A-aDO2, Torr 2.8

3.016.5

8.1*23.1

7.0*26.9

5.5*28.9

7.6*32.0

8.1*11.3

9.226.3

14.2*29.6

11.9*34.6

10.7*35.4

11.6*37.7

12.8*pH 7.40

0.017.38

0.03*7.32

0.04*7.26

0.05*7.23

0.06*7.21

0.07*7.41

0.017.39

0.02*7.32

0.02*7.27

0.02*7.26

0.06*7.24

0.08*HCO3

, mmol/l 23.8 1.7

22.0 1.4

19.2 1.3*

16.0 1.7*

14.0 1.6*

12.2 0.8*

23.3 2.6

22.3 3.2

18.8 2.2*

16.4 1.3*

15.3 3.0*

13.8 3.1*

BE, mmol/l 0.5 1.4

2.4 1.9*

6.2 1.8*

10.2 2.4*

12.5 2.5*

14.8 1.8*

0.7 2.1

2.0 2.7*

6.4 2.1*

9.5 1.0*

10.6 3.7*

12.5 4.2*

Values are means SD. PaO2, arterial PO2; PaCO2, arterial PCO2; A-aDO2, alveolar-arterial difference for O2; BE, base excess. *Significantlydifferent from rest (P 0.05).



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hypoxic exercise in athletes with EIH. Unique to this

investigation was the observation that inhalation of 20ppm NO during normoxic and hypoxic high-intensity,short-duration exercise did not significantly affect gasexchange, VO2, or cycling power in highly trained ath-letes with EIH.

The mechanism(s) of EIH remains controversial.However, VA/Q inequality and diffusion limitationsmay be causative (6, 11, 30). The mechanisms explain-ing the increases in VA/Q inequality and diffusion lim-itation are unknown but may be related to the devel-opment of transient pulmonary edema (6). Someauthors have suggested that, in elite athletes, theintegrity of the pulmonary blood-gas barrier is alteredat extreme levels of exercise (29). However, identifica-

tion of pulmonary edema and pulmonary stress failurehas been difficult to achieve in exercising humans andremains controversial. Although the specific mecha-nism for VA/Q inequality and diffusion limitations isdebatable, the end result is a widened A-aDO2. InhaledNO, a selective pulmonary vasodilator (8, 9), is used inthe treatment of diseases characterized by pulmonaryhypertension and hypoxemia (1, 15, 16). The rationaleis based on the fact that NO, given by inhalation, onlydilates those pulmonary vessels that are well venti-

lated. As a result, pulmonary gas exchange is im

proved. We hypothesized that inhaled NO would improved gas exchange in athletes with EIH.Inhaled NO during normoxia. The present investi

gation demonstrated no differences in gas exchangeVO2, power, or heart rate between N and N/NO at restor during exercise. These findings do not support ouroriginal hypothesis but do agree with observations inresting sheep (17) and the fact that PaO

2was not

altered in normal individuals who inhaled NO at rest(8). In addition, our findings are consistent with datathat reported no effects of inhaled NO on Q or DLCO inhumans (2) or PaO

2

and VA/Q in dogs (12) under normoxic conditions.

Studies that have sought to examine the effects o

inhaled NO during exercise in humans have been fewTo date, only one group (7) has investigated the effectsof NO inhalation on pulmonary gas exchange duringexercise in highly trained athletes. In agreement withthe present study, they observed no differences for ventilatory and performance parameters. Howeverthey found that inhalation of NO caused PaO

2

to decrease at rest and during exercise compared withbreathing room air. This is in contrast to the presentstudy and the resting data of Frostell et al. (8). It is

Fig. 2. Arterial PO2 (PaO2) during rest and at each minute of 5-mincycle ergometry tests under condition N (s), N/NO (), H (F), andH/NO (E). Values are means SD. *N and N/NO are significantlydifferent from resting condition (rest) (P 0.05). H and H/NOsignificantly different from rest (P 0.05).

Fig. 3. Percent arterial oxyhemoglobin saturation (SaO2) during resand at each minute of 5-min cycle ergometry tests under condition N(s), N/NO (), H (F), and H/NO (E). Values are means SD. *N andN/NO are significantly different from rest (P 0.05). H and H/NOsignificantly different from rest (P 0.05).

Table 6. Blood variables during hypoxic and hypoxic NO 5-min cycle ergometry

Hypoxia Hypoxia NO

Rest

Minute

Rest

Minute

1 2 3 4 5 1 2 3 4 5

PaO2, Torr 66.7 5.4

47.4* 4.9

44.3 5.3*

44.2 5.2*

43.3 4.2*

44.3 3.4*

64.3 6.6

44.9 3.3*

43.3 3.4*

42.6 3.6*

42.0 2.4*

42.3 2.2

SaO2, % 93.7 1.4

84.0 4.3*

79.0 4.9*

78.2 4.5*

74.9 5.6*

74.7 4.3*

93.5 4.0

82.1 1.9*

78.1 1.6*

75.6 1.8*

72.2 1.9*

71.2 1.9

PaCO2, Torr 37.6 4.0

34.9 3.0*

33.7 2.3*

31.7 1.2*

30.1 1.2*

29.3 2.4*

35.9 6.0

33.4 4.9

32.9 5.0

31.6 4.3*

29.7 4.1*

29.0 3.8

A-aDO2, Torr 2.0 2.2

15.8 8.6*

21.0 11.5*

23.9 7.2*

26.3 6.9*

25.6 6.8*

1.4 1.9

20.5 7.0*

24.3 6.2*

25.3 5.7*

26.9 6.6*

26.7 6.8

pH 7.42 0.02

7.41 0.02

7.36 0.04*

7.33 0.04*

7.29 0.05*

7.26 0.07*

7.41 0.02

7.41 0.03

7.37 0.03*

7.32 0.04*

7.28 0.04*

7.25 0.04*

HCO3, mmol/l 24.1

2.122.0

2.019.2

1.9*16.8

1.9*15.0

1.9*13.7

2.3*22.6

4.021.3

3.318.4

2.4*15.9

1.8*13.9

1.7*12.4

1.4BE, mmol/l 0.3

1.61.9 1.3*

5.4 2.0*

8.0 2.1*

10.4 2.7*

12.2 3.5*

0.7 3.3

1.4 2.2

5.6 2.0*

8.6 1.6*

11.2 1.7*

13.3 1.6

Values are means SD. *Significantly different from rest (P 0.05).



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important to note that arterial blood-gas measure-ments were corrected for temperature in the presentstudy, whereas those of Durand et al. (7) were not. Thiswould likely overestimate the drop in PaO

2

and SaO2

they observed during exercise and impact on the inter-pretation of their results.

Although pulmonary pressures were not measuredin this study, we can speculate on two possible expla-

nations for our normoxic results: 1) pulmonary pres-sures were not altered or 2) pulmonary pressures werereduced with no effect on gas exchange. We believe it ismore probable that the first scenario occurred, al-though we cannot exclude the second possibility. Thepulmonary capillary bed in these athletes may havebeen already maximally dilated, and inhalation of avasodilator would have no further effect. Therefore, noeffect on pulmonary pressure would be expected norwould any alteration in gas exchange occur. Our re-sults are therefore consistent with the hypothesis ofDempsey (4), who postulated that pulmonary capillaryblood volume reaches its maximal morphological limitand further dilation is not anatomically possible. How-

ever, in light of our lack of hemodynamic measures, weemphasize the speculative nature of this explanation ofour negative findings.

Inhaled NO during hypoxia. Unique to this investi-gation was the delivery of NO to individuals with EIHduring hypoxic exercise. As expected, during H andH/NO, PaO

2

and SaO2

were significantly lower than Nand N/NO at all time points (Figs. 2 and 3). The drop inoxygenation during hypoxic exercise was consistentwith that observed in previous EIH studies (22). Sim-ilar to the normoxic trials, inhaled NO did not alter gasexchange, VO2, or cycling power during hypoxia. Pisonet al. (21) showed that addition of 20 ppm NO to a

hypoxic (FIO2 12%) gas mixture returned pulmonarygas-exchange measures to baseline values in mechan-ically ventilated sheep. These are in contrast to ourresults in which no statistical difference was observedfor gas-exchange variables between H and H/NO. Thiswas an unexpected result; we expected that HPV wouldbe induced by using a hypoxic inspiratory gas mixtureat rest and during exercise.

We hypothesized that inhaled NO would have re- versed the transient HPV and improved pulmonarygas exchange, as demonstrated in healthy humansbreathing hypoxic gas (21). Why did we observe noeffect of NO on gas exchange during the resting hy-poxic condition? Potentially, the HPV at rest in the

present study was of a small enough magnitude andduration to have had a minimal effect on gas exchange.However, this seems unlikely given that the timecourse for HPV has a distinct initial rapid constrictionthat reaches a peak within minutes and shows pro-found increases in pulmonary vascular resistancewithin the time frame used in the present study (28).An alternate explanation is that the timing of restingsamples impacted on arterial blood-gas values. Restingsamples were taken after a warm-up period thatwas preceded by a 5-min resting period. Possibly, thewarm-up influenced the VA/Q relationship and may

explain the lack of effect of NO on gas exchangeFurthermore, subjects may have been slightly hyperventilating at the time of the resting sample (PaCO

2

o3638 Torr), which could have affected the influenceof NO.

The lack of effect of NO during hypoxic exercise isconsistent with the observations of Koizumi et al. (17)Inhalation of NO during exercise in sheep had no effect

on PaO2. In addition, inhaled NO did not change thetime course or magnitude of changes in pulmonarypressures in the exercising sheep.

Limitations of the study. A debatable point is howmuch of the inhaled NO actually reached the lowerairways? Although it was not possible to measure theamount of inhaled NO that reaches the alveoli, weassume that subjects in the present study did indeedinhale 20 ppm NO. We are confident that NO wasdelivered to the respiratory system, as it was measured5 cm from the point of inspiration. The experimentalapproach and NO concentration employed in our studywere similar to those employed by others (7). It ispossible that the concentration of NO used in this

study was not sufficient to induce vasodilation; however, this seems unlikely given that similar concentrations have been used previously to show significanalterations in gas exchange and pulmonary pressures(19, 21, 25). Our choice of 20 ppm was based on theabove-mentioned studies and other clinical investigations.

It is possible that we failed to detect a statisticadifference between conditions due to our small samplesize and insufficient statistical power. However, thisseems unlikely. Post hoc statistical power (1 calculations were performed utilizing a computer statistical program for gas-exchange variables across nor

moxic and hypoxic conditions. Power values rangedfrom 0.72 to 0.84, indicating sufficient protectionagainst type II errors.

Determination of pulmonary artery pressure andcardiac output in the present study, together with VA/Qmeasures, would have allowed for more definitive conclusions on the effect of inhaled NO during exerciseBecause the use of NO was hypothesized to act as aselective pulmonary vasodilator, the lack of the measurement of pulmonary artery and wedge pressuresrepresents a major limitation of this study.

In summary, we have demonstrated that inhalationof 20 ppm NO during normoxic and hypoxic highintensity, short-duration cycle exercise did not signifi

cantly affect gas exchange in athletes with EIH. Cardiorespiratory variables and cycling power output werealso unaffected by NO inhalation during normoxia andhypoxia. We conclude that inhalation of 20 ppm NOduring normoxic and hypoxic exercise has no effect ongas exchange in highly trained cyclists.

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