Short-arm centrifugation as a partially effective musculoskeletal countermeasure during 5-day head-down tilt bed rest--results from the BRAG1 study.

PURPOSE: Human centrifugation, also called artificial gravity (AG), is proposed as a combined strategy against detrimental effects of microgravity in long-term space missions. This study scrutinized human short-arm centrifugation as countermeasure against musculoskeletal de-conditioning. METHOD: Eleven healthy male subjects [mean age of 34 (SD 7) years] completed the cross-over trial, including three campaigns of -6° head-down tilt bed rest (HDT) for 5 days, with preceding baseline data collection and recovery phases. Bed rest without AG was used as control condition (Ctrl), and AG with 1 g at the center of mass applied once per day for 30 min in one bout (AG1×30) and in 6 bouts of 5 min (AG6×5, 3-min rest between bouts) as experimental conditions. End-points were muscle strength, vertical jump performance, and biomarkers of bone and protein metabolism. RESULT: AG6×5 was better tolerated than AG1×30. Bone resorption markers CTX, NTX, and DPD all increased by approximately 25 % toward the end of bed rest (P < 0.001), and nitrogen balance decreased by approximately 3 g/day (P < 0.001), without any protection by AG (P > 0.4). Decreases in vertical jump height by 2.1 (SE 0.6) cm after Ctrl bed rest was prevented by either of the AG protocols (P = 0.039). CONCLUSION: The present study yielded succinct catabolic effects upon muscle and bone metabolism that were un-prevented by AG. The preservation of vertical jump performance by AG in this study is likely caused by central nervous rather than by peripheral musculoskeletal effects.

Pulmonary nitric oxide in astronauts before and during long-term spaceflight.

Introduction: During exploratory space flights astronauts risk exposure to toxic planetary dust. Exhaled nitric oxide partial pressure (PENO) is a simple method to monitor lung health by detecting airway inflammation after dust inhalation. The turnover of NO in the lungs is dependent on several factors which will be altered during planetary exploration such as gravity (G) and gas density. To investigate the impacts of these factors on normal PENO, we took measurements before and during a stay at the International Space Station, at both normal and reduced atmospheric pressures. We expected stable PENO levels during the preflight and inflight periods, with lower values inflight. With reduced pressure we expected no net changes of PENO. Material and methods: Ten astronauts were studied during the pre-flight (1 G) and inflight (µG) periods at normal pressure [1.0 ata (atmospheres absolute)], with six of them also monitored at reduced (0.7 ata) pressure and gas density. The average observation period was from 191 days before launch until 105 days after launch. PENO was measured together with estimates of alveolar NO and the airway contribution to the exhaled NO flux. Results: The levels of PENO at 50 mL/s (PENO50) were not stable during the preflight and inflight periods respectively but decreased with time (p = 0.0284) at a rate of 0.55 (0.24) [mean (SD)] mPa per 180 days throughout the observation period, so that there was a significant difference (p < 0.01, N = 10) between gravity conditions. Thus, PENO50 averaged 2.28 (0.70) mPa at 1 G and 1.65 (0.51) mPa during µG (-27%). Reduced atmospheric pressure had no net impact on PENO50 but increased the airway contribution to exhaled NO. Discussion: The time courses of PENO50 suggest an initial airway inflammation, which gradually subsided. Our previous hypothesis of an increased uptake of NO to the blood by means of an expanded gas-blood interface in µG leading to decreased PENO50 is neither supported nor contradicted by the present findings. Baseline PENO50 values for lung health monitoring in astronauts should be obtained not only on ground but also during the relevant gravity conditions and before the possibility of inhaling toxic planetary dust.

Lung diffusing capacity for nitric oxide in space: microgravity gas density interactions.

Introduction: During manned space exploration lung health is threatened by toxic planetary dust and radiation. Thus, tests such as lung diffusing capacity (DL) are likely be used in planetary habitats to monitor lung health. During a DL maneuver the rate of uptake of an inspired blood-soluble gas such as nitric oxide (NO) is determined (DLNO). The aim of this study was to investigate the influence of altered gravity and reduced atmospheric pressure on the test results, since the atmospheric pressure in a habitat on the moon or on Mars is planned to be lower than on Earth. Changes of gravity are known to alter the blood filling of the lungs which in turn may modify the rate of gas uptake into the blood, and changes of atmospheric pressure may alter the speed of gas transport in the gas phase. Methods: DLNO was determined in 11 subjects on the ground and in microgravity on the International Space Station. Experiments were performed at both normal (1.0 atm absolute, ata) and reduced (0.7 ata) atmospheric pressures. Results: On the ground, DLNO did not differ between pressures, but in microgravity DLNO was increased by 9.8% (9.5) (mean [SD]) and 18.3% (15.8) at 1.0 and 0.7 ata respectively, compared to normal gravity, 1.0 ata. There was a significant interaction between pressure and gravity (p = 0.0135). Discussion: Estimates of the membrane (DmNO) and gas phase (DgNO) components of DLNO suggested that at normal gravity a reduced pressure led to opposing effects in convective and diffusive transport in the gas phase, with no net effect of pressure. In contrast, a DLNO increase with reduced pressure at microgravity is compatible with a substantial increase of DmNO partially offset by reduced DgNO, the latter being compatible with interstitial edema. In microgravity therefore, DmNO would be proportionally underestimated from DLNO. We also conclude that normal values for DL in anticipation of planetary exploration should be determined not only on the ground but also at the gravity and pressure conditions of a future planetary habitat.

Effects of acceleration in the Gz axis on human cardiopulmonary responses to exercise.

The aim of this paper was to develop a model from experimental data allowing a prediction of the cardiopulmonary responses to steady-state submaximal exercise in varying gravitational environments, with acceleration in the G(z) axis (a (g)) ranging from 0 to 3 g. To this aim, we combined data from three different experiments, carried out at Buffalo, at Stockholm and inside the Mir Station. Oxygen consumption, as expected, increased linearly with a (g). In contrast, heart rate increased non-linearly with a (g), whereas stroke volume decreased non-linearly: both were described by quadratic functions. Thus, the relationship between cardiac output and a (g) was described by a fourth power regression equation. Mean arterial pressure increased with a (g) non linearly, a relation that we interpolated again with a quadratic function. Thus, total peripheral resistance varied linearly with a (g). These data led to predict that maximal oxygen consumption would decrease drastically as a (g) is increased. Maximal oxygen consumption would become equal to resting oxygen consumption when a (g) is around 4.5 g, thus indicating the practical impossibility for humans to stay and work on the biggest Planets of the Solar System.

Regional lung blood flow and ventilation in upright humans studied with quantitative SPECT.

We used quantitative Single Photon Emission Computed Tomography (SPECT) to study the effect of the upright posture on regional lung blood flow and ventilation. Nine (upright) plus seven (prone and supine) healthy volunteers were studied awake, breathing spontaneously. Regional blood flow and ventilation were marked in sitting upright, supine and prone postures using (113m)In-labeled macroaggregates and inhaled Technegas ((99m)Tc); both remain fixed in the lung after administration. All images were obtained while supine. In comparison with horizontal postures, both blood flow and ventilation were greater in caudal regions when upright. The redistribution was greater for blood flow than for ventilation, resulting in decreasing ventilation-to-perfusion ratios down the lung when upright. We conclude that gravity redistributes regional blood flow and ventilation in the upright posture, while the influence is much less in the supine and prone postures.

Influence of combined exercise and gravity transients and apnea on hemodynamics.

Hemodynamic responses to combined heavy dynamic leg exercise (hiP), breath holding (BH) and gravity-induced blood volume shifts direction were studied. Thirteen subjects were studied at normal gravity and 12 during parabolic flight, performing 20 s hiP or combined hiP&BH (stimulus period) from a baseline of 30 W at normal gravity (1 G(z+)). Heart rate and mean arterial pressure responses to BH were similar between gravity conditions, but stroke volume (SV) differed markedly between gravity conditions: at 1 G(z+) SV was higher [112 +/- 16 ml (mean +/- SD)] during BH, than during eupnea [101 +/- 17 ml (P < 0.05, N = 13)]. In weightlessness the corresponding SV values were 105 +/- 16 and 127 +/- 20 ml, respectively (P < 0.05, N = 6). Transthoracic electrical conductance (TTC) was used as index for intrathoracic volume. TTC fell significantly during BH. This decrease was attenuated in weightlessness. It is concluded that the transient microgravity temporarily reduces the efficiency of the muscle pump so that the deep inspiration at the onset of the high-intensity exercise and breath-hold period cannot augment venous return as it could during identical manoeuvres at normal gravity.

Posture primarily affects lung tissue distribution with minor effect on blood flow and ventilation.

We used quantitative single photon emission computed tomography to estimate the proportion of the observed redistribution of blood flow and ventilation that is due to lung tissue shift with a change in posture. Seven healthy volunteers were studied awake, breathing spontaneously. Regional blood flow and ventilation were marked using radiotracers that remain fixed in the lung after administration. The radiotracers were administered in prone or supine at separate occasions, at both occasions followed by imaging in both postures. Images showed greater blood flow and ventilation to regions dependent at the time of imaging, regardless of posture at radiotracer administration. The results suggest that a shift in lung parenchyma has a major influence on the imaged distributions. We conclude that a change from the supine to the prone posture primarily causes a change in the vertical distribution of lung tissue. The effect on the vertical distribution of blood flow and ventilation within the lung parenchyma is much less.

Paradoxical redistribution of pulmonary blood flow in prone and supine humans exposed to hypergravity.

We hypothesized that exposure to hypergravity in the supine and prone postures causes a redistribution of pulmonary blood flow to dependent lung regions. Four normal subjects were exposed to hypergravity by use of a human centrifuge. Regional lung perfusion was estimated by single-photon-emission computed tomography (SPECT) after administration of (99m)Tc-labeled albumin macroaggregates during normal and three times normal gravity conditions in the supine and prone postures. All images were obtained during normal gravity. Exposure to hypergravity caused a redistribution of blood flow from dependent to nondependent lung regions in all subjects in both postures. We speculate that this unexpected and paradoxical redistribution is a consequence of airway closure in dependent lung regions causing alveolar hypoxia and hypoxic vasoconstriction. Alternatively, increased vascular resistance in dependent lung regions is caused by distortion of lung parenchyma. The redistribution of blood flow is likely to attenuate rather than contribute to the arterial desaturation caused by hypergravity.

Non-invasive continuous estimation of blood flow changes in human patellar bone.

A photoplethysmographic (PPG) technique to assess blood flow in bone tissue has been developed and tested. The signal detected by the PPG consists of a constant-level (DC) component-which is related to the relative vascularization of the tissue-and a pulsatile (AC) component-which is synchronous with the pumping action of the heart. The PPG probe was applied on the skin over the patella. The probe uses near-infrared (804 nm) and green (560 nm) light sources and the AC component of the PPG signals of the two wavelengths was used to monitor pulsatile blood flow in the patellar bone and the overlying skin, respectively. Twenty healthy subjects were studied and arterial occlusion resulted in elimination of PPG signals at both wavelengths, whereas occlusion of skin blood flow by local surface pressure eliminated only the PPG signal at 560 nm. In a parallel study on a physical model with a rigid tube we showed that the AC component of the PPG signal originates from pulsations of blood flow in a rigid structure and not necessarily from volume pulsations. We conclude that pulsatile blood flow in the patellar bone can be assessed with the present PPG technique.

Effects of gravity and blood volume shifts on cardiogenic oscillations in respired gas.

During the cardiac cycle, cardiogenic oscillations of expired gas (x) concentrations (COS([x])) are generated. At the same time, there are heart-synchronous cardiogenic oscillations of airway flow (COS(flow)), where inflow occurs during systole. We hypothesized that both phenomena, although primarily generated by the heartbeat, would react differently to the cephalad blood shift caused by inflation of an anti-gravity (anti-G) suit and to changes in gravity. Twelve seated subjects performed a rebreathing-breath-holding-expiration maneuver with a gas mixture containing O2 and He at normal (1 G) and moderately increased gravity (2 G); an anti-G suit was inflated to 85 mmHg in each condition. When the anti-G suit was inflated, COS(flow) amplitude increased (P = 0.0028) at 1 G to 186% of the control value without inflation (1-G control) and at 2 G to 203% of the control value without inflation (2-G control). In contrast, the amplitude of COS of the concentration of the blood-soluble gas O2 (COS([O2/He])), an index of the differences in pulmonary perfusion between lung units, declined to 75% of the 1-G control value and to 74% of the 2-G control value (P = 0.0030). There were no significant changes in COS(flow) or COS([O2/He]) amplitudes with gravity. We conclude that the heart-synchronous mechanical agitation of the lungs, as expressed by COS(flow), is highly dependent on peripheral-to-central blood shifts. In contrast, COS([blood-soluble gas]) appears relatively independent of this mechanical agitation and seems to be determined mainly by differences in intrapulmonary perfusion.

Residual heterogeneity of intra- and interregional pulmonary perfusion in short-term microgravity.

We hypothesized that the perfusion heterogeneity in the human, upright lung is determined by nongravitational more than gravitational factors. Twelve and six subjects were studied during two series of parabolic flights. We used cardiogenic oscillations of O(2)/SF(6) as an indirect estimate of intraregional perfusion heterogeneity (series 1) and phase IV amplitude (P(4)) as a indirect estimate of interregional perfusion heterogeneity (series 2). A rebreathing-breath holding-expiration maneuver was performed. In flight, breath holding and expiration were performed either in microgravity (0 G) or in hypergravity. Controls were performed at normal gravity (1 G). In series 1, expiration was performed at 0 G. Cardiogenic oscillations of O(2)/SF(6) were 19% lower when breath holding was performed at 0 G than when breath holding was performed at 1 G [means (SD): 1.7 (0.3) and 2.3 (0.6)% units] (P = 0.044). When breath holding was performed at 1.8 G, values did not differ from 1-G control [2.6 (0.8)% units, P = 0.15], but they were 17% larger at 1.8 G than at 1 G. In series 2, expiration was performed at 1.7 G. P(4) changed with gravity (P < 0.001). When breath holding was performed at 0 G, P(4) values were 45 (46)% of control. When breath holding was performed at 1.7 G, P(4) values were 183 (101)% of control. We conclude that more than one-half of indexes of perfusion heterogeneity at 1 G are caused by nongravitational mechanisms.

Long-term bed rest-induced reductions in stroke volume during rest and exercise: cardiac dysfunction vs. volume depletion.

Long-term head-down-tilt bed rest (HDT) causes cardiovascular deconditioning, attributed to reflex dysfunctions, plasma volume reduction, or cardiac impairments. Our objective with the present study was to evaluate the functional importance and relative contribution of these during rest and exercise in supine and upright postures. We studied six subjects before (baseline), during [days 60 (D60) and 113 (D113)], and after [recovery days 0 (R0), 3 (R3), and 15 (R15)] 120 days of -6 degrees HDT. We determined cardiac output, stroke volume (SV), mean arterial pressure, and heart rate during rest and exercise in supine and upright postures. Cardiac output and SV decreased significantly in all four conditions, but the time courses differed for rest and exercise. Upright resting SV was decreased by 24 +/- 9% at D60 compared with baseline but had recovered already at R3. Supine exercise SV decreased more slowly (by 5 +/- 8% at D60 and by 18 +/- 4% at D113) and recovered more slowly after HDT termination. Steady-state mean arterial pressure showed no changes. Heart rate had increased by 18 +/- 4% at D60 and had recovered partially at R3. Our data indicate that long-term HDT causes both a rapid, preload-dependent reduction in SV, most evident during rest in the upright position, and a more slowly developing cardiac dysfunction, most evident during supine exercise. However, the ability to maintain blood pressure and to perform sustained low levels of dynamic exercise is not influenced by HDT.

Effects of an artificial gravity countermeasure on orthostatic tolerance, blood volumes and aerobic power after short-term bed rest (BR-AG1).

Exposure to artificial gravity (AG) in a short-arm centrifuge has potential benefits for maintaining human performance during long-term space missions. Eleven subjects were investigated during three campaigns of 5 days head-down bed rest: 1) bed rest without countermeasures (control), 2) bed rest and 30 min of AG (AG1) daily, and 3) bed rest and six periods of 5 min AG (AG2) daily. During centrifugation, the supine subjects were exposed to AG in the head-to-feet direction with 1 G at the center of mass. Subjects participated in the three campaigns in random order. The cardiovascular effects of bed rest and countermeasures were determined from changes in tolerance to a head-up tilt test with superimposed lower body negative pressure (HUT), from changes in plasma volume (PV) and from changes in maximum aerobic power (V̇o2 peak) during upright work on a cycle ergometer. Complete data sets were obtained in eight subjects. After bed rest, HUT tolerance times were 36, 64, and 78% of pre-bed rest baseline during control, AG1 and AG2, respectively, with a significant difference between AG2 and control. PV and V̇o2 peak decreased to 85 and 95% of pre-bed rest baseline, respectively, with no differences between the treatments. It was concluded that the AG2 countermeasure should be further investigated during future long-term bed rest studies, especially as it was better tolerated than AG1. The superior effect of AG2 on orthostatic tolerance could not be related to concomitant changes in PV or aerobic power.

Differential changes of lung diffusing capacity and tissue volume in hypergravity.

In normal gravity, lung diffusing capacity (DL(CO)) and lung tissue volume (LTV; including pulmonary capillary blood volume) change in concert, for example, during shifts between upright and supine. Accordingly, DL(CO) and LTV might be expected to decrease together in sitting subjects in hypergravity due to peripheral pooling of blood and reduced central blood volume. Nine sitting subjects in a human centrifuge were exposed to one, two, and three times increased gravity in the head-to-feet direction (G(z+)) and rebreathed a gas containing trace amounts of acetylene and carbon monoxide. DL(CO) was 25.2 +/- 2.6, 20.0 +/- 2.1, and 16.7 +/- 1.7 ml. min(-1). mbar(-1) (means +/- SE) at 1, 2, and 3 G(z+), respectively (ANOVA P < 0.001). Corresponding values for LTV increased from 541 +/- 34 to 677 +/- 43, and 756 +/- 71 ml (P < 0.001) at 2 and 3 G(z+). Results are compatible with sequestration of blood in the dependent part of the pulmonary circulation just as in the systemic counterpart. DL(CO,) which under normoxic conditions is mainly determined by its membrane component, decreased despite an increased pulmonary capillary blood volume, most likely as a consequence of a less homogenous distribution of alveolar volume with respect to pulmonary capillary blood volume.

Effects of hypergravity on the distributions of lung ventilation and perfusion in sitting humans assessed with a simple two-step maneuver.

Increased gravity impairs pulmonary distributions of ventilation and perfusion. We sought to develop a method for rapid, simultaneous, and noninvasive assessments of ventilation and perfusion distributions during a short-duration hypergravity exposure. Nine sitting subjects were exposed to one, two, and three times normal gravity (1, 2, and 3 G) in the head-to-feet direction and performed a rebreathing and a single-breath washout maneuver with a gas mixture containing C(2)H(2), O(2), and Ar. Expirograms were analyzed for cardiogenic oscillations (COS) and for phase IV amplitude to analyze inhomogeneities in ventilation (Ar) and perfusion [CO(2)-to-Ar ratio (CO(2)/Ar)] distribution, respectively. COS were normalized for changes in stroke volume. COS for Ar increased from 1-G control to 128 +/- 6% (mean +/- SE) at 2 G (P = 0.02 for 1 vs. 2 G) and 165 +/- 13% at 3 G (P = 0.002 for 2 vs. 3 G). Corresponding values for CO(2)/Ar were 135 +/- 12% (P = 0.04) and 146 +/- 13%. Phase IV amplitude for Ar increased to 193 +/- 39% (P = 0.008) at 2 G and 229 +/- 51% at 3 G compared with 1 G. Corresponding values for CO(2)/Ar were 188 +/- 29% (P = 0.02) and 219 +/- 18%. We conclude that not only large-scale ventilation and perfusion inhomogeneities, as reflected by phase IV amplitude, but also smaller-scale inhomogeneities, as reflected by the ratio of COS to stroke volume, increase with hypergravity. Except for small-scale ventilation distribution, most of the impairments observed at 3 G had been attained at 2 G. For some of the parameters and gravity levels, previous comparable data support the present simplified method.

Lung function during and after prolonged head-down bed rest.

We determined the effects of prolonged head-down tilt bed rest (HDT) on lung mechanics and gas exchange. Six subjects were studied in supine and upright postures before (control), during [day 113 (D113)], and after (R + number of days of recovery) 120 days of HDT. Peak expiratory flow (PF) never differed between positions at any time and never differed from controls. Maximal midexpiratory flow (FEF(25-75%)) was lower in the supine than in the upright posture before HDT and was reduced in the supine posture by about 20% between baseline and D113, R + 0, and R + 3. The diffusing capacity for carbon monoxide corrected to a standardized alveolar volume (volume-corrected DL(CO)) was lower in the upright than in the supine posture and decreased in both postures by 20% between baseline and R + 0 and by 15% between baseline and R + 15. Pulmonary blood flow (Q(C)) increased from R + 0 to R + 3 by 20 (supine) and 35% (upright). As PF is mostly effort dependent, our data speak against major respiratory muscle deconditioning after 120 days of HDT. The decrease in FEF(25-75%) suggests a reduction in elastic recoil. Time courses of volume-corrected DL(CO) and Q(C) could be explained by a decrease in central blood volume during and immediately after HDT.

Physiological evaluation of a new quantitative SPECT method measuring regional ventilation and perfusion.

We have developed a new quantitative single-photon-emission computed tomography (SPECT) method that uses (113m)In-labeled albumin macroaggregates and Technegas ((99m)Tc) to estimate the distributions of regional ventilation and perfusion for the whole lung. The multiple inert-gas elimination technique (MIGET) and whole lung respiratory gas exchange were used as physiological evaluations of the SPECT method. Regional ventilation and perfusion were estimated by SPECT in nine healthy volunteers during awake, spontaneous breathing. Radiotracers were administered with subjects sitting upright, and SPECT images were acquired with subjects supine. Whole lung gas exchange of MIGET gases and arterial Po(2) and Pco(2) gases was predicted from estimates of regional ventilation and perfusion. We found a good agreement between measured and SPECT-predicted exchange of MIGET and respiratory gases. Correlations (r(2)) between SPECT-predicted and measured inert-gas excretions and retentions were 0.99. The method offers a new tool for measuring regional ventilation and perfusion in humans.

Relationship between breath-synchronous arterial pressure and heart rate variations during orthostatic stress.

It has recently been shown that the phase relationship between respiration-induced changes in arterial pressure (AP) and heart rate (HR) are different in supine and upright postures. We wanted to further analyse the coupling between respiration, arterial blood pressure and HR in the time domain, and how this coupling was altered during orthostatic stress. Nine healthy subjects were studied. Respiration-induced changes in AP and HR were recorded during frequency- and volume-controlled breathing. This was done during supine rest with and without lower body negative pressure (-50 mmHg) (LBNP). All experiments were performed after beta1-blockade. Responses were averaged breath-by-breath to enhance the time resolution and to eliminate noise. The respiration-induced changes in arterial pulse pressure (PP) were different between control and LBNP: The peak in PP during the respiratory cycle occurred 0.9 +/- 0.8 (mean +/- SD) s before the onset of inspiration during supine control and 0.8 +/- 2.1 s after the onset of inspiration during LBNP (P = 0.03). These changes in the timing of peak PP significantly distorted the cyclic systolic AP and mean AP fluctuations during LBNP. Despite the altered AP response with LBNP, HR fluctuations closely correlated in time with respiration in all conditions, albeit with a significantly reduced amplitude during LBNP (-49%, P = 0.01). The results points to a lack of coupling between AP and HR during paced breathing and thus suggest that respiratory sinus dysrhythmia at least, to a large extent, is independent of the arterial baroreflex.

Lung diffusing capacity for nitric oxide at lowered and raised ambient pressures.

Lung diffusing capacity for NO (DLNO) was determined in eight subjects at ambient pressures of 505, 1015, and 4053hPa (379, 761 and 3040mmHg) as they breathed normoxic gases. Mean values were 116.9±11.1 (SEM), 113.4±11.1 and 99.3±10.1mlmin(-1)hPa(-1)at 505, 1015, and 4053hPa, with a 13% difference between the two higher pressures (P=0.017). The data were applied to a model with two serially coupled conductances; the gas phase (DgNO, variable with pressure), and the alveolo-capillary membrane (DmNO, constant). The data fitted the model well and we conclude that diffusive transport of NO in the peripheral lung is inversely related to gas density. At normal pressure DmNO was approximately 5% larger than DLNO, suggesting that the Dg factor then is not negligible. We also conclude that the density of the breathing gas is likely to impact the backdiffusion of naturally formed NO from conducting airways to the alveoli.

Effects of ambient pressure on pulmonary nitric oxide.

Airway nitric oxide (NO) has been proposed to play a role in the development of high-altitude pulmonary edema. We undertook a study of the effects of acute changes of ambient pressure on exhaled and alveolar NO in the range 0.5-4 atmospheres absolute (ATA, 379-3,040 mmHg) in eight healthy subjects breathing normoxic nitrogen-oxygen mixtures. On the basis of previous work with inhalation of low-density helium-oxygen gas, we expected facilitated backdiffusion and lowered exhaled NO at 0.5 ATA and the opposite at 4 ATA. Instead, the exhaled NO partial pressure (Pe(NO)) did not differ between pressures and averaged 1.21 ± 0.16 (SE) mPa across pressures. As a consequence, exhaled NO fractions varied inversely with pressure. Alveolar estimates of the NO partial pressure differed between pressures and averaged 88 (P = 0.04) and 176 (P = 0.009) percent of control (1 ATA) at 0.5 and 4 ATA, respectively. The airway contribution to exhaled NO was reduced to 79% of control (P = 0.009) at 4 ATA. Our finding of the same Pe(NO) at 0.5 and 1 ATA is at variance with previous findings of a reduced Pe(NO) with inhalation of low-density gas at normal pressure, and this discrepancy may be due to the much longer durations of low-density gas breathing in the present study compared with previous studies with helium-oxygen breathing. The present data are compatible with the notion of an enhanced convective backtransport of NO, compensating for attenuated backdiffusion of NO with increasing pressure. An alternative interpretation is a pressure-induced suppression of NO formation in the airways.