Diffusional screening in the human pulmonary acinus.

In the mammalian lung acini, O(2) diffuses into quasi-static air toward the alveolar membrane, where the gas exchange with blood takes place. The O(2) flux is then influenced by the O(2) diffusivity, the membrane permeability, and the acinus geometric complexity. This phenomenon has been recently studied in an abstract geometric model of the acinus, the Hilbert acinus (Sapoval B, Filoche M, and Weibel ER, Proc Natl Acad Sci USA 99: 10411, 2002). This is extended here to a more realistic geometry originated from the morphological model of Kitaoka et al. (Kitaoka K, Tamura S, and Takaki R, J Appl Physiol 88: 2260-2268, 2000). Two-dimensional numerical simulations of the steady-state diffusion equation with mixed boundary conditions are used to quantify the process. The alveolar O(2) concentration, or partial pressure, and the O(2) flux are computed and show that diffusional screening exists at rest. These results confirm that smaller acini are more efficient, as suggested for the Hilbert acini.     

Pulmonary gas exchange at maximal exercise in Danish lowlanders during 8 wk of acclimatization to 4,100 m and in high-altitude Aymara natives

We aimed to test effects of altitude acclimatization on pulmonary gas exchange at maximal exercise. Six lowlanders were studied at sea level, in acute hypoxia (AH), and after 2 and 8 wk of acclimatization to 4,100 m (2W and 8W) and compared with Aymara high-altitude natives residing at this altitude. As expected, alveolar Po2 was reduced during AH but increased gradually during acclimatization (61 +/- 0.7, 69 +/- 0.9, and 72 +/- 1.4 mmHg in AH, 2W, and 8W, respectively), reaching values significantly higher than in Aymaras (67 +/- 0.6 mmHg). Arterial Po2 (PaO2) also decreased during exercise in AH but increased significantly with acclimatization (51 +/- 1.1, 58 +/- 1.7, and 62 +/- 1.6 mmHg in AH, 2W, and 8W, respectively). PaO2 in lowlanders reached levels that were not different from those in high-altitude natives (66 +/- 1.2 mmHg). Arterial O2 saturation (SaO2) decreased during maximum exercise compared with rest in AH and after 2W and 8W: 73.3 +/- 1.4, 76.9 +/- 1.7, and 79.3 +/- 1.6%, respectively. After 8W, SaO2 in lowlanders was not significantly different from that in Aymaras (82.7 +/- 1%). An improved pulmonary gas exchange with acclimatization was evidenced by a decreased ventilatory equivalent of O2 after 8W: 59 +/- 4, 58 +/- 4, and 52 +/- 4 l x min x l O2(-1), respectively. The ventilatory equivalent of O2 reached levels not different from that of Aymaras (51 +/- 3 l x min x l O2(-1)). However, increases in exercise alveolar Po2 and PaO2 with acclimatization had no net effect on alveolar-arterial Po2 difference in lowlanders (10 +/- 1.3, 11 +/- 1.5, and 10 +/- 2.1 mmHg in AH, 2W, and 8W, respectively), which remained significantly higher than in Aymaras (1 +/- 1.4 mmHg). In conclusion, lowlanders substantially improve pulmonary gas exchange with acclimatization, but even acclimatization for 8 wk is insufficient to achieve levels reached by high-altitude natives.     

Pulmonary gas exchange in humans during normobaric hypoxic exercise

Previous studies (J. Appl. Physiol. 58: 978-988 and 989-995, 1985) have shown both worsening ventilation-perfusion (VA/Q) relationships and the development of diffusion limitation during heavy exercise at sea level and during hypobaric hypoxia in a chamber [fractional inspired O2 concentration (FIO2) = 0.21, minimum barometric pressure (PB) = 429 Torr, inspired O2 partial pressure (PIO2) = 80 Torr]. We used the multiple inert gas elimination technique to compare gas exchange during exercise under normobaric hypoxia (FIO2 = 0.11, PB = 760 Torr, PIO2 = 80 Torr) with earlier hypobaric measurements. Mixed expired and arterial respiratory and inert gas tensions, cardiac output, heart rate (HR), minute ventilation, respiratory rate (RR), and blood temperature were recorded at rest and during steady-state exercise in 10 normal subjects in the following order: rest, air; rest, 11% O2; light exercise (75 W), 11% O2; intermediate exercise (150 W), 11% O2; heavy exercise (greater than 200 W), 11% O2; heavy exercise, 100% O2 and then air; and rest 20 minutes postexercise, air. VA/Q inequality increased significantly during hypoxic exercise [mean log standard deviation of perfusion (logSDQ) = 0.42 +/- 0.03 (rest) and 0.67 +/- 0.09 (at 2.3 l/min O2 consumption), P less than 0.01]. VA/Q inequality was improved by relief of hypoxia (logSDQ = 0.51 +/- 0.04 and 0.48 +/- 0.02 for 100% O2 and air breathing, respectively). Diffusion limitation for O2 was evident at all exercise levels while breathing 11% O2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reducing lung strain after pneumonectomy impairs oxygen diffusing capacity but not ventilation-perfusion matching.

After pneumonectomy (Pnx), mechanical strain on the remaining lung is an important signal for adaptation. To examine how mechanical lung strain alters gas exchange adaptation after Pnx, we replaced the right lung of adult dogs with a custom-shaped inflatable silicone prosthesis. The prosthesis was kept 1) inflated (Inf) to reduce mechanical strain of the remaining lung and maintain the mediastinum in the midline, or 2) deflated (Def) to allow lung strain and mediastinal shift. Gas exchange was studied 4-7 mo later at rest and during treadmill exercise by the multiple inert gas elimination technique while animals breathed 21 and 14% O2 in balanced order. In the Inf group compared with Def group during hypoxic exercise, arterial O2 saturation was lower and alveolar-arterial O2 tension difference higher, whereas O2 diffusing capacity was lower at any given cardiac output. Dispersion of the perfusion distribution was similar between groups at rest and during exercise. Dispersion of the ventilation distribution was lower in the Inf group at rest, associated with a much higher respiratory rate, but rose to similar levels in both groups during hypoxic exercise. Mean pulmonary arterial pressure at a given cardiac output was higher in the Inf group, whereas peak cardiac output was similar between groups. Thus creating lung strain by post-Pnx mediastinal shift primarily enhances diffusive gas exchange with only minor effects on ventilation-perfusion matching, consistent with the generation of additional alveolar-capillary surfaces but not conducting airways and blood vessels.     

Shifting sources of functional limitation following extensive (70%) lung resection.

We previously found that, following surgical resection of approximately 58% of lung units by right pneumonectomy (PNX) in adult canines, oxygen-diffusing capacity (Dl(O(2))) fell sufficiently to become a major factor limiting exercise capacity, although the decline was mitigated by recruitment, remodeling, and growth of the remaining lung units. To determine whether an upper limit of compensation is reached following the loss of even more lung units, we measured pulmonary gas exchange, hemodynamics, and ventilatory power requirements in adult canines during treadmill exercise following two-stage resection of approximately 70% of lung units in the presence or absence of mediastinal distortion. Results were compared with that in control animals following right PNX or thoracotomy without resection (Sham). Following 70% lung resection, peak O(2) uptake was 45% below normal. Ventilation-perfusion mismatch developed, and pulmonary arterial pressure and ventilatory power requirements became markedly elevated. In contrast, the relationship of Dl(O(2)) to cardiac output remained normal, indicating preservation of Dl(O(2))-to-cardiac output ratio and alveolar-capillary recruitment up to peak exercise. The impairment in airway and vascular function exceeded the impairment in gas exchange and imposed the major limitation to exercise following 70% resection. Mediastinal distortion further reduced air and blood flow conductance, resulting in CO(2) retention. Results suggest that adaptation of extra-acinar airways and blood vessels lagged behind that of acinar tissue. As more lung units were lost, functional compensation became limited by the disproportionately reduced convective conductance rather than by alveolar diffusion disequilibrium.     

Carbon dioxide added late in inspiration reduces ventilation-perfusion heterogeneity without causing respiratory acidosis.

We have shown previously that inspired CO2 (3-5%) improves ventilation-perfusion (Va/Q) matching but with the consequence of mild arterial hypercapnia and respiratory acidosis. We hypothesized that adding CO2 only late in inspiration to limit its effects to the conducting airways would enhance Va/Q matching and improve oxygenation without arterial hypercapnia. CO2 was added in the latter half of inspiration in a volume aimed to reach a concentration of 5% in the conducting airways throughout the respiratory cycle. Ten mixed-breed dogs were anesthetized and, in a randomized order, ventilated with room air, 5% CO2 throughout inspiration, and CO2 added only to the latter half of inspiration. The multiple inert-gas elimination technique was used to assess Va/Q heterogeneity. Late-inspired CO2 produced only very small changes in arterial pH (7.38 vs. 7.40) and arterial CO2 (40.6 vs. 39.4 Torr). Compared with baseline, late-inspired CO2 significantly improved arterial oxygenation (97.5 vs. 94.2 Torr), decreased the alveolar-arterial Po2 difference (10.4 vs. 15.7 Torr) and decreased the multiple inert-gas elimination technique-derived arterial-alveolar inert gas area difference, a global measurement of Va/Q heterogeneity (0.36 vs. 0.22). These changes were equal to those with 5% CO2 throughout inspiration (arterial Po2, 102.5 Torr; alveolar-arterial Po2 difference, 10.1 Torr; and arterial-alveolar inert gas area difference, 0.21). In conclusion, we have established that the majority of the improvement in gas exchange efficiency with inspired CO2 can be achieved by limiting its application to the conducting airways and does not require systemic acidosis.     

Reverse Engineering of Oxygen Transport in the Lung: Adaptation to Changing Demands and Resources through Space-Filling Networks

The space-filling fractal network in the human lung creates a remarkable distribution system for gas exchange. Landmark studies have illuminated how the fractal network guarantees minimum energy dissipation, slows air down with minimum hardware, maximizes the gas- exchange surface area, and creates respiratory flexibility between rest and exercise. In this paper, we investigate how the fractal architecture affects oxygen transport and exchange under varying physiological conditions, with respect to performance metrics not previously studied.We present a renormalization treatment of the diffusion-reaction equation which describes how oxygen concentrations drop in the airways as oxygen crosses the alveolar membrane system. The treatment predicts oxygen currents across the lung at different levels of exercise which agree with measured values within a few percent. The results exhibit wide-ranging adaptation to changing process parameters, including maximum oxygen uptake rate at minimum alveolar membrane permeability, the ability to rapidly switch from a low oxygen uptake rate at rest to high rates at exercise, and the ability to maintain a constant oxygen uptake rate in the event of a change in permeability or surface area. We show that alternative, less than space-filling architectures perform sub-optimally and that optimal performance of the space-filling architecture results from a competition between underexploration and overexploration of the surface by oxygen molecules.     

Gas exchange during exercise in habitually active asthmatic subjects.

We determined the relations among gas exchange, breathing mechanics, and airway inflammation during moderate- to maximum-intensity exercise in asthmatic subjects. Twenty-one habitually active (48.2 +/- 7.0 ml.kg(-1).min(-1) maximal O2 uptake) mildly to moderately asthmatic subjects (94 +/- 13% predicted forced expiratory volume in 1.0 s) performed treadmill exercise to exhaustion (11.2 +/- 0.15 min) at approximately 90% of maximal O2 uptake. Arterial O2 saturation decreased to < or =94% during the exercise in 8 of 21 subjects, in large part as a result of a decrease in arterial Po2 (PaO2): from 93.0 +/- 7.7 to 79.7 +/- 4.0 Torr. A widened alveolar-to-arterial Po2 difference and the magnitude of the ventilatory response contributed approximately equally to the decrease in PaO2 during exercise. Airflow limitation and airway inflammation at baseline did not correlate with exercise gas exchange, but an exercise-induced increase in sputum histamine levels correlated with exercise Pa(O2) (negatively) and alveolar-to-arterial Po2 difference (positively). Mean pulmonary resistance was high during exercise (3.4 +/- 1.2 cmH2O.l(-1).s) and did not increase throughout exercise. Expiratory flow limitation occurred in 19 of 21 subjects, averaging 43 +/- 35% of tidal volume near end exercise, and end-expiratory lung volume rose progressively to 0.25 +/- 0.47 liter greater than resting end-expiratory lung volume at exhaustion. These mechanical constraints to ventilation contributed to a heterogeneous and frequently insufficient ventilatory response; arterial Pco2 was 30-47 Torr at end exercise. Thus pulmonary gas exchange is impaired during high-intensity exercise in a significant number of habitually active asthmatic subjects because of high airway resistance and, possibly, a deleterious effect of exercise-induced airway inflammation on gas exchange efficiency.     

Breath-by-breath alveolar gas exchange

A method is described for breath-by-breath measurement of alveolar gas exchange corrected for changes of lung gas stores. In practice, the subject inspires from a spirometer, and each expired tidal volume is collected into a rubber bag placed inside a rigid box connected to the same spirometer. During the inspiration following any given expiration the bag is emptied by a vacuum pump. A computer monitors inspiratory and expiratory tidal volumes, drives four solenoid valves allowing appropriate operation of the system, and memorizes end-tidal gas fractions as well as mixed expired gas composition analyzed by mass spectrometer. Thus all variables for calculating alveolar gas exchange, based on the theory developed by Auchincloss et al. (J. Appl. Physiol. 21: 810-818, 1966), are obtained on a single-breath basis. Mean resting and steady-state exercise gas exchange data are equal to those obtained by conventional open-circuit measurements. Breathing rates up to 30 X min-1 can be followed. The breath-to-breath variability of O2 uptake at the alveolar level is less (25-35%) than that measured at the mouth as the difference between the inspired and expired volumes, both at rest and during exercise up to 0.7 of maximum O2 consumption.     

Effect of a patent foramen ovale on pulmonary gas exchange efficiency at rest and during exercise

The prevalence of a patent foramen ovale (PFO) is ~30%, and this source of right-to-left shunt could result in greater pulmonary gas exchange impairment at rest and during exercise. The aim of this work was to determine if individuals with an asymptomatic PFO (PFO+) have greater pulmonary gas exchange inefficiency at rest and during exercise than subjects without a PFO (PFO-). Separated by 1 h of rest, 8 PFO+ and 8 PFO- subjects performed two incremental cycle ergometer exercise tests to voluntary exhaustion while breathing either room air or hypoxic gas [fraction of inspired O(2) (FI(O(2))) = 0.12]. Using echocardiography, we detected small, intermittent boluses of saline contrast bubbles entering directly into the left atrium within 3 heart beats at rest and during both exercise conditions in PFO+. These findings suggest a qualitatively small intracardiac shunt at rest and during exercise in PFO+. The alveolar-to-arterial oxygen difference (AaDo(2)) was significantly (P < 0.05) different between PFO+ and PFO- in normoxia (5.9 ± 5.1 vs. 0.5 ± 3.5 mmHg) and hypoxia (10.1 ± 5.9 vs. 4.1 ± 3.1 mmHg) at rest, but not during exercise. However, arterial oxygen saturation was significantly different between PFO+ and PFO- at peak exercise in normoxia (94.3 ± 0.9 vs. 95.8 ± 1.0%) as a result of a significant difference in esophageal temperature (38.4 ± 0.3 vs. 38.0 ± 0.3°C). An asymptomatic PFO contributes to pulmonary gas exchange inefficiency at rest but not during exercise in healthy humans and therefore does not explain intersubject variability in the AaDO(2) at maximal exercise.     

Ventilation-perfusion inequality during normoxic and hypoxic exercise in the emu.

Many avian species exhibit an extraordinary ability to exercise under hypoxic condition compared with mammals, and more efficient pulmonary O(2) transport has been hypothesized to contribute to this avian advantage. We studied six emus (Dromaius novaehollandaie, 4-6 mo old, 25-40 kg) at rest and during treadmill exercise in normoxia and hypoxia (inspired O(2) fraction approximately 0.13). The multiple inert gas elimination technique was used to measure ventilation-perfusion (V/Q) distribution of the lung and calculate cardiac output and parabronchial ventilation. In both normoxia and hypoxia, exercise increased arterial Po(2) and decreased arterial Pco(2), reflecting hyperventilation, whereas pH remained unchanged. The V/Q distribution was unimodal, with a log standard deviation of perfusion distribution = 0.60 +/- 0.06 at rest; this did not change significantly with either exercise or hypoxia. Intrapulmonary shunt was <1% of the cardiac output in all conditions. CO(2) elimination was enhanced by hypoxia and exercise, but O(2) exchange was not affected by exercise in normoxia or hypoxia. The stability of V/Q matching under conditions of hypoxia and exercise may be advantageous for birds flying at altitude.     

Spatial distribution of hypoxic pulmonary vasoconstriction in the supine pig.

Hypoxic pulmonary vasoconstriction (HPV) serves to maintain optimal gas exchange by decreasing perfusion to hypoxic regions. However, global hypoxia and nonuniform HPV may result in overperfusion of poorly constricted regions leading to local edema seen in high-altitude pulmonary edema. To quantify the spatial distribution of HPV and its response to regional Po2 (Pr(O2)) among small lung regions, five pigs were anesthetized and mechanically ventilated in the supine posture. The animals were ventilated with an inspired O2 fraction (Fi(O2)) of 0.50 and 0.21 and then (in random order) 0.15, 0.12, and 0.09. Regional blood flow (Q) and alveolar ventilation (Va) were measured by using intravenous infusion of 15 microm and inhalation of 1-microm fluorescent microspheres, respectively. Pr(O2) was calculated for each piece at each Fi(O2). Lung pieces differed in their Q response to hypoxia in a manner related to their initial Va/Q with Fi(O2) = 0.21. Reducing Fi(O2) < 0.15 decreased Q to the initially high Va/Q (higher Pr(O2)) regions and forced Q into the low Va/Q (dorsal-caudal) regions. Resistance increased in most lung pieces as Pr(O2) decreased, reaching a maximum resistance when Pr(O2) is between 40 and 50 Torr. Local resistance decreased at PrO2 < 40 Torr. Pieces were statistically clustered with respect to their relative Q response pattern to each Fi(O2). Some clusters were shown to be spatially organized. We conclude that HPV is spatially heterogeneous. The heterogeneity of Q response may be related, in part, to the heterogeneity of baseline Va/Q.     

Effects of inhaled nitric oxide at rest and during exercise in idiopathic pulmonary fibrosis

Patients with idiopathic pulmonary fibrosis (IPF) usually develop hypoxemia and pulmonary hypertension when exercising. To what extent endothelium-derived vasodilating agents modify these changes is unknown. The study was aimed to investigate in patients with IPF whether exercise induces changes in plasma levels of endothelium-derived signaling mediators, and to assess the acute effects of inhaled nitric oxide (NO) on pulmonary hemodynamics and gas exchange, at rest and during exercise. We evaluated seven patients with IPF (6 men/1 woman; 57 ± 11 yr; forced vital capacity, 60 ± 13% predicted; carbon monoxide diffusing capacity, 52 ± 10% predicted). Levels of endothelin, 6-keto-prostaglandin-F(1α), thromboxane B(2), and nitrates were measured at rest and during submaximal exercise. Pulmonary hemodynamics and gas exchange, including ventilation-perfusion relationships, were assessed breathing ambient air and 40 ppm NO, both at rest and during submaximal exercise. The concentration of thromboxane B(2) increased during exercise (P = 0.046), whereas levels of other mediators did not change. The change in 6-keto-prostaglandin-F(1α) correlated with that of mean pulmonary arterial pressure (r = 0.94; P < 0.005). Inhaled NO reduced mean pulmonary arterial pressure at rest (-4.6 ± 2.1 mmHg) and during exercise (-11.7 ± 7.1 mmHg) (P = 0.001 and P = 0.004, respectively), without altering arterial oxygenation or ventilation-perfusion distributions in any of the study conditions. Alveolar-to-capillary oxygen diffusion limitation, which accounted for the decrease of arterial Po(2) during exercise, was not modified by NO administration. We conclude that, in IPF, some endothelium-derived signaling molecules may modulate the development of pulmonary hypertension during exercise, and that the administration of inhaled NO reduces pulmonary vascular resistance without disturbing gas exchange.     

Effect of regional alveolar hypoxia on gas exchange in dogs

We studied the effects of left lower lobe (LLL) alveolar hypoxia on pulmonary gas exchange in anesthetized dogs using the multiple inert gas elimination technique (MIGET). The left upper lobe was removed, and a bronchial divider was placed. The right lung (RL) was continuously ventilated with 100% O2, and the LLL was ventilated with either 100% O2 (hyperoxia) or a hypoxic gas mixture (hypoxia). Whole lung and individual LLL and RL ventilation-perfusion (VA/Q) distributions were determined. LLL hypoxia reduced LLL blood flow and increased the perfusion-related indexes of VA/Q heterogeneity, such as the log standard deviation of the perfusion distribution (log SDQ), the retention component of the arterial-alveolar difference area [R(a-A)D], and the retention dispersion index (DISPR*) of the LLL. LLL hypoxia increased blood flow to the RL and reduced the VA/Q heterogeneity of the RL, indicated by significant reductions in log SDQ, R(a-A)D, and DISPR*. In contrast, LLL hypoxia had little effect on gas exchange of the lung when evaluated as a whole. We conclude that flow diversion induced by regional alveolar hypoxia preserves matching of ventilation to perfusion in the whole lung by increasing gas exchange heterogeneity of the hypoxic region and reducing heterogeneity in the normoxic lung.     

Regenerative growth of respiratory bronchioles in dogs

Loss of lung units due to pneumonectomy stimulates growth of the remaining lung. It is generally believed that regenerative lung growth involves only alveoli but not airways, a dissociated response termed "dysanaptic growth." We examined the structural response of respiratory bronchioles in immature dogs raised to maturity after right pneumonectomy. In another group of adult dogs, we also examined the effect of preventing mediastinal shift after right pneumonectomy on the response of respiratory bronchioles. In immature dogs after pneumonectomy, the volume of the remaining lung increased twofold, with no change in volume density, numerical density, or mean diameter of respiratory bronchiole, compared with that in the control lung. The number of respiratory bronchiole segments and branch points increased proportionally with lung volume. In adult dogs after pneumonectomy, prevention of mediastinal shift reduced lung strain at a given airway pressure, but lung expansion and regenerative growth of respiratory bronchiole were not eliminated. We conclude that postpneumonectomy lung growth is associated with proliferation of intra-acinar airways. The proportional growth of acinar airways and alveoli should optimize gas exchange of the regenerated lung by enhancing gas conductance and mixing efficiency within the acinus.     

Influence of Bohr-Haldane effect on steady-state gas exchange

The influence of the Bohr-Haldane effect (BH) on steady-state gas exchange has previously been described by its effect of gas transfer from the blood when arterial and venous blood gas tensions were held constant. This report quantifies by computer analysis the effects of BH when either or both arterial and venous blood gas tensions are subject to change. When mixed venous blood gas composition is held constant, elimination of BH from a single lung unit typically reduces CO2 output by 6.5% and O2 uptake by 0.5%. Similar effects occur in a two-compartment lung model whether alveolar ventilation-perfusion (VA/Q) mismatch occurs in a parallel or series ventilatory arrangement. When arterial blood gas composition is held constant, elimination of BH increases systemic venous CO2 partial pressure, but O2 partial pressure is hardly affected in the absence of metabolic acidosis. When both mixed venous and arterial blood gas tensions vary and gas exchange is stressed by VA/Q inequality, altitude, anemia, or exercise, elimination of BH predominantly affects mixed venous rather than arterial blood gas tensions. it is concluded that BH may act primarily to reduce tissue acidosis.     

Intrapulmonary shunting and pulmonary gas exchange during normoxic and hypoxic exercise in healthy humans.

Exercise-induced intrapulmonary arteriovenous shunting, as detected by saline contrast echocardiography, has been demonstrated in healthy humans. We have previously suggested that increases in both pulmonary pressures and blood flow associated with exercise are responsible for opening these intrapulmonary arteriovenous pathways. In the present study, we hypothesized that, although cardiac output and pulmonary pressures would be higher in hypoxia, the potent pulmonary vasoconstrictor effect of hypoxia would actually attenuate exercise-induced intrapulmonary shunting. Using saline contrast echocardiography, we examined nine healthy men during incremental (65 W + 30 W/2 min) cycle exercise to exhaustion in normoxia and hypoxia (fraction of inspired O(2) = 0.12). Contrast injections were made into a peripheral vein at rest and during exercise and recovery (3-5 min postexercise) with pulmonary gas exchange measured simultaneously. At rest, no subject demonstrated intrapulmonary shunting in normoxia [arterial Po(2) (Pa(O(2))) = 98 +/- 10 Torr], whereas in hypoxia (Pa(O(2)) = 47 +/- 5 Torr), intrapulmonary shunting developed in 3/9 subjects. During exercise, approximately 90% (8/9) of the subjects shunted during normoxia, whereas all subjects shunted during hypoxia. Four of the nine subjects shunted at a lower workload in hypoxia. Furthermore, all subjects continued to shunt at 3 min, and five subjects shunted at 5 min postexercise in hypoxia. Hypoxia has acute effects by inducing intrapulmonary arteriovenous shunt pathways at rest and during exercise and has long-term effects by maintaining patency of these vessels during recovery. Whether oxygen tension specifically regulates these novel pathways or opens them indirectly via effects on the conventional pulmonary vasculature remains unclear.     

Effect of hyperoxia and hypoxia on leg blood flow and pulmonary and leg oxygen uptake at the onset of kicking exercise

The purpose of this study was to examine the interactions of adaptations in O2 transport and utilization under conditions of altered arterial O2 content (CaO2), during rest to exercise transitions. Simultaneous measures of alveolar (VO2alv) and leg (VO2mus) oxygen uptake and leg blood flow (LBF) responses were obtained in normoxic (FiO2 (inspired fraction of O2) = 0.21), hypoxic (FiO2 = 0.14), and hyperoxic (FiO2 = 0.70) gas breathing conditions. Six healthy subjects performed transitions in leg kicking exercise from rest to 48 +/- 3 W. LBF was measured continuously with pulsed and echo Doppler ultrasound methods, VO2alv was measured breath-by-breath at the mouth and VO2mus was determined from LBF and radial artery and femoral vein blood samples. Even though hypoxia reduced CaO2 to 175.9 +/- 5.0 from 193.2 +/- 5.0 mL/L in normoxia, and hyperoxia increased CaO2 to 205.5 +/- 4.1 mL/L, there were no differences in the absolute values of VO2alv or VO2mus across gas conditions at any of the rest or exercise time points. A reduction in leg O2 delivery in hypoxia at the onset of exercise was compensated by a nonsignificant increase in O2 extraction and later by small increases in LBF to maintain VO2mus. The dynamic response of VO2alv was slower in the hypoxic condition; however, hyperoxia did not affect the responses of oxygen delivery or uptake at the onset of moderate intensity leg kicking exercise. The finding of similar VO2mus responses at the onset of exercise for all gas conditions demonstrated that physiological adaptations in LBF and O2 extraction were possible, to counter significant alterations in CaO2. These results show the importance of the interplay between O2 supply and O2 utilization mechanisms in meeting the challenge provided by small alterations in O2 content at the onset of this submaximal exercise task.     

Supramaximal exercise after training-induced hypervolemia. I. Gas exchange and acid-base balance

The effect of an exercise-induced reduction in blood O2-carrying capacity on ventilatory gas exchange and acid-base balance during supramaximal exercise was studied in six males [peak O2 consumption (VO2peak), 3.98 +/- 0.49 l/min]. Three consecutive days of supramaximal exercise resulted in a preexercise reduction of hemoglobin concentration from 15.8 to 14.0 g/dl (P less than 0.05). During exercise (120% VO2peak) performed intermittently (1 min work to 4 min rest); a small but significant (P less than 0.05) increase was found for both O2 consumption (VO2) (l X min) and heart rate (beats/min) on day 2 of the training. On day 3, VO2 (l/min) was reduced 3.2% (P less than 0.05) over day 1 values. No changes were found in CO2 output and minute ventilation during exercise between training days. Similarly, short-term training failed to significantly alter the changes in arterialized blood PCO2, pH, and [HCO-3] observed during exercise. It is concluded that hypervolemia-induced reductions in O2-carrying capacity in the order of 10-11% cause minimal impairment to gas exchange and acid-base balance during supramaximal non-steady-state exercise.     

Effects of crocetin on pulmonary gas exchange in foxhounds during hypoxic exercise.

The carotenoid compound crocetin has been hypothesized to enhance the diffusion of O(2) through plasma, and observations in the rat and rabbit have revealed improvement in arterial PO(2) when crocetin is given. To determine whether crocetin enhances diffusion of O(2) between alveolar gas and the red blood cell in the pulmonary capillary in vivo, five foxhounds, two previously subjected to sham and three to actual lobectomy or pneumonectomy, were studied while breathing 14% O(2) at rest and during moderate and heavy exercise before and within 10 min after injection of a single dose of crocetin as the trans isomer of sodium crocetinate (TSC) at 100 microg/kg iv. This dose is equivalent to that used in previous studies and would yield an initial plasma concentration of 0.7-1.0 microg/ml. Ventilation-perfusion inequality and pulmonary diffusion limitation were assessed by the multiple inert gas elimination technique in concert with conventional measurements of arterial and mixed venous O(2) and CO(2). TSC had no effect on ventilation, cardiac output, O(2) consumption, arterial PO(2)/saturation, or pulmonary O(2) diffusing capacity. There were minor reductions in ventilation-perfusion mismatching (logarithm of the standard deviation of perfusion fell from 0.48 to 0.43, P = 0.001) and in CO(2) output and respiratory exchange ratio (P = 0.05), which may have been due to TSC or to persisting effects of the first exercise bout. Spectrophotometry revealed that TSC disappeared from plasma with a half time of approximately 10 min. We conclude that, in this model of extensive pulmonary O(2) diffusion limitation, TSC as given has no effect on O(2) exchange or transport. Whether the original hypothesis is invalid, the dose of TSC was too low, or plasma diffusion of O(2) is not rate limiting without TSC cannot be discerned from the present study.