Journal of Applied Physiology AJP: Heart and Circulatory Physiology
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J Appl Physiol 102: 1448-1455, 2007. First published January 11, 2007; doi:10.1152/japplphysiol.00971.2006
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Residence at 3,800-m altitude for 5 mo in growing dogs enhances lung diffusing capacity for oxygen that persists at least 2.5 years

Connie C. W. Hsia,1 Robert L. Johnson, Jr,1 Paul McDonough,1 D. Merrill Dane,1 Myresa D. Hurst,1 Jennifer L. Fehmel,1 Harrieth E. Wagner,2 and Peter D. Wagner2

1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and 2Department of Medicine, University of California, San Diego, La Jolla, California

Submitted 3 September 2006 ; accepted in final form 15 November 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Mammals native to high altitude (HA) exhibit larger lung volumes than their lowland counterparts. To test the hypothesis that adaptation induced by HA residence during somatic maturation improves pulmonary gas exchange in adulthood, male foxhounds born at sea level (SL) were raised at HA (3,800 m) from 2.5 to 7.5 mo of age and then returned to SL prior to somatic maturity while their littermates were simultaneously raised at SL. Following return to SL, all animals were trained to run on a treadmill; gas exchange and hemodynamics were measured 2.5 years later at rest and during exercise while breathing 21% and 13% O2. The multiple inert gas elimination technique was employed to estimate ventilation-perfusion (VA/Q) distributions and lung diffusing capacity for O2 (DLO2). There were no significant intergroup differences during exercise breathing 21% O2. During exercise breathing 13% O2, peak O2 uptake and VA/Q distributions were similar between groups but arterial pH, base excess, and O2 saturation were higher while peak lactate concentration was lower in animals raised at HA than at SL. At a given exercise intensity, alveolar-arterial O2 tension gradient (A-aDO2) attributable to diffusion limitation was lower while DLO2 was 12–25% higher in HA-raised animals. Mean systemic arterial blood pressure was also lower in HA-raised animals; mean pulmonary arterial pressures were similar. We conclude that 5 mo of HA residence during maturation enhances long-term gas exchange efficiency and DLO2 without impacting VA/Q inequality during hypoxic exercise at SL.

hypoxia; ventilation-perfusion distribution; multiple inert gas elimination technique; oxygen diffusing capacity; exercise

THERE IS A SIZABLE BODY of literature showing that lung volume, vital capacity, gas exchange, and lung diffusing capacity are larger in native highlanders compared with lowlanders (6, 7, 11, 15, 16, 18, 19, 23, 35, 44, 56). Exercise performance and pulmonary gas exchange at altitude are also better in native highlanders than in acclimatized lowlanders (12, 13, 52, 56). While it is not clear if the changes observed in human subjects are the result of genetic predisposition or induced by high-altitude (HA) residence, data from animal studies support residence at a moderate HA as a stimulus of postnatal alveolar development (4, 8, 9, 30, 45, 46). In dogs born at sea level (SL) but raised for 14 mo to maturity at 3,100 m altitude, lung volume and diffusing capacity for carbon monoxide (DLCO) measured at rest are higher than in matched control animals raised simultaneously at SL; the findings were attributable to larger alveolar tissue volume and surface area while somatic growth and thoracic dimensions were not altered (20, 31, 32). In the same study, adult dogs kept at 3,100 m altitude for 3 years showed no change in resting DLCO, alveolar tissue volume, or surface area (20, 31, 32). It seems that moderate HA accentuates active lung growth during maturation, but is insufficient by itself to reinitiate lung growth in the absence of developmental stimuli in the adult animal. The intensity or duration of HA exposure required for the induction of functional improvement is unknown. It is also unclear whether the higher DLCO measured at rest in HA-raised animals persists upon exercise.

We reasoned that if growing animals adapt readily to HA residence they should also adapt with equal vigor to the withdrawal of the HA stimulus. We wondered whether more limited HA exposure during somatic maturation enhances gas exchange and exercise performance at SL and whether such improvement is permanent. Therefore, we performed a set of studies to determine 1) whether HA residence during maturation improves long-term pulmonary gas exchange during exercise and 2) whether HA-induced adaptation partly or completely reverses when animals return to SL prior to somatic maturity. To address these issues, we raised young foxhounds (2.5 mo of age) at 3,800 m altitude for 5 mo and then returned them to SL at 7.5 mo of age, i.e., before reaching somatic maturity. In the first study (40), we found persistently elevated lung volume, DLCO, membrane diffusing capacity, and pulmonary capillary blood volume at rest and during exercise in HA-raised animals compared with litter-matched controls raised at SL when measured 1–2 years following return to SL. We concluded that a relatively short period of HA residence during maturation permanently enhanced lung function into adulthood. In this second study we addressed these questions in the same animals. 1) Does the elevated DLCO in HA-raised animals correspond to a lower alveolar-arterial O2 tension gradient (A-aDO2) and enhanced O2 diffusing capacity (DLO2)? 2) Does HA residence during maturation alter long-term ventilation-perfusion (VA/Q) relationships? 3) Does HA residence during maturation improve long-term maximal O2 uptake (VO2 max)? About 2.5 years after animals returned to SL, we determined their VO2 max, hemodynamic function, VA/Q distributions, and DLO2 during exercise while breathing 21% and 13% O2. We found that while breathing 13% O2, animals raised at HA showed a persistently lower A-aDO2 attributable to diffusion limitation and a persistently higher DLO2, which allowed VO2 max to be achieved at an improved metabolic efficiency compared with control animals raised at SL.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Animals.   The Institutional Animal Care and Use Committees of the University of Texas Southwestern Medical Center and the University of California White Mountain Research Station both approved the protocols. Six pairs of purpose-bred, litter-matched male mixed-breed foxhounds born at SL were used (total 12 animals). At 2.5 mo of age, one animal from each pair was randomly selected and transported to HA at the Barcroft Laboratory (altitude 3,800 m, barometric pressure 485 mmHg) of the University of California White Mountain Research Station and remained there for 5 mo. Their six male littermates were raised simultaneously at SL in Dallas, TX (altitude ~156 m, barometric pressure 750 mmHg). Animals were fed similar diet and given water ad libitum. All animals acclimatized readily to HA. Body weight was measured each week. At 7.5 mo of age, the animals residing at HA returned to SL in Dallas. Physiological studies of lung function and circulating blood volume were performed at rest 1 mo later and reported previously (40). Then the animals were trained to run on a motorized treadmill according to an established exercise program (47); training continued throughout the duration of the study. A customized leak-free respiratory mask was made for each animal to allow for ventilatory and gas exchange measurements during exercise (1). Bilateral carotid artery loops were surgically constructed to allow acute arterial catheterization (41). Cardiopulmonary function, including lung volume, pulmonary blood flow, DLCO, and its components membrane diffusing capacity and pulmonary capillary blood volume, were assessed at rest and during exercise by a noninvasive rebreathing method between 1 and 2 years following return to SL. Circulating blood volume and resting cardiopulmonary function were measured again 2 years after returning to SL; these results have been reported elsewhere (40). The present invasive studies were performed ~2.5 years after returning to SL.

Apparatus.   The animal breathed through a two-way respiratory valve (#2700, Hans Rudolph, Kansas City, MO). The inspiratory port was connected through a screen pneumotachometer (Hans Rudolph #3813) to either room air or a meteorological balloon containing 13% O2 to simulate 3,800 m altitude. The expiratory port led to a mixing chamber and another heated screen pneumotachometer; expired flow was integrated to obtain tidal volume. Expired gas concentrations were sampled continuously from a port located distal to the mixing chamber by a mass spectrometer (MGA 1100, Perkin-Elmer). The pneumotachometer-computer system was calibrated on the day of study (55). Electrocardiogram and rectal temperature were continuously monitored. Signals were digitized at 100 Hz. Ventilation (l/min), O2 uptake (ml/min), CO2 production (ml/min), tidal volume (ml), respiratory rate, and heart rate were averaged every 10 breaths. Pulmonary and systemic vascular pressures were recorded using identical fluid-filled transducers (Statham Instruments, P23 ID) via Hewlett-Packard carrier amplifiers and digitized. Pressure transducers were calibrated using a mercury manometer on the day of study.

Maximal O2 uptake.   Room temperature was kept at 19°C. On the day of study the carotid artery was cannulated under local anesthesia while the animal stood in a restraining sling. Ventilatory parameters, rectal temperature, and heart rate were continuously recorded. With the dog standing on the treadmill, a baseline blood sample (2 ml) was drawn to measure hematocrit, hemoglobin, and lactate concentrations. After 5 min of warm-up exercise at 6 miles/h 0% grade, the treadmill speed was increased to 8 mph and the grade was increased by 5% every 3 min until the animal could not keep up with the treadmill or until rectal temperature exceeded 41°C or heart rate exceeded 300 beats/min. A blood sample (2 ml) was taken during the last 30 s of each workload and every 2 min for 6 min following cessation of exercise for measurement of blood gases (Radiometer, ABL-500, Copenhagen, Denmark), hemoximetry (Radiometer, model OSM3), hematocrit by a capillary microcentrifuge (International, model MB), and lactate concentration (YSI 1500 Sport, Yellow Spring Instruments, Yellow Springs, OH). The incremental exercise protocol was repeated with the animal breathing 21 or 13% O2 on separate days.

Hemodynamic measurements.   On a separate day and with the animal standing in a sling, a 5-Fr catheter was inserted under local anesthesia into the exteriorized carotid artery and advanced into the aorta for monitoring systemic arterial blood pressure and drawing blood samples. An 8.5-Fr introducer was inserted into each external jugular vein. A balloon-tipped triple-lumen thermal dilution catheter was inserted through one jugular introducer into the pulmonary artery for monitoring blood temperature and pressure and for drawing mixed venous blood; catheter position was confirmed from pressure tracings. The opposite jugular venous introducer was used for infusion of dissolved inert gases (multiple inert gas elimination technique). Catheters were sutured to the skin and flushed with heparinized saline. All vascular pressures were referenced to that measured by a fluid-filled reference catheter sutured to the skin of the lateral chest at the level of the right atrium midway between the sternum and the spine. Pulmonary arterial blood temperature was monitored using a cardiac output computer (Arrow International, Reading, PA) and recorded each minute. Cardiac output was determined by the direct Fick method from measured O2 uptake and arterial and mixed venous PO2 and O2 saturation. The VA/Q distributions were measured by the multiple inert gas elimination technique below.

Multiple inert gas elimination technique.   We employed this technique as previously described (27, 29, 54). Six inert gases with different solubility (SF6, ethane, cyclopropane, enflurane, acetone, and ether) were dissolved in saline and infused at a constant rate via one jugular venous catheter at an infusion rate maintained ~1/4,000th of the dog's minute ventilation under all conditions to ensure an adequate signal-to-noise ratio. At rest, the infusion began 20 min before sampling. Upon exercise, equilibrium of inert gas exchange at the blood-gas interface is achieved rapidly; therefore, sampling was performed after 3 min of infusion. Baseline measurements were made with the dog standing on the treadmill. After 5 min of warm-up exercise (6 miles/h 0% grade), the workload was increased quickly to a preselected level equivalent to 50 or 80% of the animal's previously measured maximal O2 uptake and sustained for ~4 min. By the end of the 3rd min at a given workload, duplicate arterial blood samples (7 ml each) and quadruplicate mixed expired gas samples (30 ml each) were collected in glass syringes for analysis of inert gas concentration by a gas chromatograph (model 5890A, Hewlett-Packard, Palo Alto, CA). Expired gas samples were collected after blood samples by a time delay equal to the time of gas transit through the mixing chamber. Blood-gas partition coefficients of the inert gases were measured in duplicate for each animal and corrected for temperature differences between the animal's blood during exercise and the water bath at which samples were equilibrated. Inert gas concentrations of mixed venous blood were calculated by mass conservation from arterial and expired values, ventilation, and cardiac output. After the inert gas samples were collected, additional arterial and mixed venous blood (2 ml each) was drawn for analysis of conventional blood gases (ABL-500, Radiometer), O2 content, hemoglobin (OSM3, Radiometer), and lactate (YSI) concentrations. Hematocrit was measured by microcapillary centrifuge. The measured PO2, PCO2, and pH were adjusted to the simultaneously measured blood temperature. After exercise, the dog cooled down by walking on the treadmill for 10 min and then rested between exercise periods until heart rate, respiratory rate, and ventilation returned to baseline. Measurements were repeated with the animal inspiring either 21 or 13% O2 in balanced order.

Data analysis.   Results were normalized by body weight and expressed as means ± SD. Measurements at peak exercise were compared between groups by one-way analysis of variance and the change from rest to exercise by repeated measures analysis of variance. Dispersion of the VA/Q distributions about the mean was quantified by the log-scale second moments with respect to ventilation (log SDV) and perfusion (log SDQ). From the inert gas data (also including values for cardiac output, ventilation, hemoglobin concentration, blood temperature, base excess, barometric pressure, inspired PO2 and PCO2, mixed venous PO2 and PCO2), the arterial PO2 (PaO2), arterial PCO2 (PaCO2), and alveolar-arterial O2 tension difference (A-aDO2) attributable to VA/Q inhomogeneity alone were determined (48). When the measured A-aDO2 exceeds that predicted from VA/Q inhomogeneity alone, the difference reflects the combined contribution to arterial hypoxemia from alveolar-end capillary diffusion impairment and postpulmonary shunting.

Breathing 21% O2 accentuates the A-aDO2 caused by VA/Q mismatch and intrapulmonary shunt while minimizing the A-aDO2 caused by diffusion impairment and extrapulmonary shunt. Breathing 13% O2 has the opposite effect (36). Differences arise because both O2 and inert gases are perturbed by VA/Q mismatch and intrapulmonary shunt, but only O2 is diffusion limited and affected by extrapulmonary shunt. Assuming for all dogs that regional DLO2 is uniformly distributed with respect to regional perfusion (Q), an estimate of the whole lung DLO2 that accounts for the difference between measured and predicted A-aDO2 at a given workload during hypoxic exercise was obtained using established algorithms (22). Because DLO2/Q inhomogeneity is assumed not to exist, this estimate of DLO2 is the smallest value that can account for the data.

The ventilatory, gas exchange, hemodynamic, VA/Q parameters as well as DLO2 obtained during submaximal exercise were plotted as a function of 1) minute ventilation, 2) O2 uptake, and/or 3) cardiac output, and the relationships were statistically compared between HA and SL groups by analysis of covariance (StatView v.5.0, SAS Institute, Cary, NC). Since we already knew that DLCO was elevated in HA-raised animals and we wished to determine if O2 diffusion improved correspondingly, a one-tailed distribution was assumed in the statistical comparisons of DLO2 and the portion of A-aDO2 attributable to diffusion limitation (measured-predicted A-aDO2). A two-tailed distribution was assumed for all other parameters. A P value of 0.05 or less was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Complete results were available from six HA and five SL animals for the determination of maximal O2 uptake, and from five HA and five SL animals for the hemodynamic measurements and determination of VA/Q distributions. One SL-raised control animal failed to exercise and was therefore removed from the study. In one HA-raised animal, the data quality was inadequate due to technical problems. Table 1 summarizes the data obtained at peak exercise using the incremental protocol. Body weight, hematocrit, hemoglobin concentration, and peak O2 uptake did not differ between HA and SL groups breathing either 21 or 13% O2. During exercise while breathing 21% O2, there were no significant differences in gas exchange and blood gas parameters between groups. During exercise while breathing 13% O2, peak O2 uptake was also not different; however, arterial pH and bicarbonate concentration were higher while minute ventilation, arterial base excess, and lactate concentration were lower at peak exercise in the HA than the SL group, consistent with better gas exchange efficiency in HA-raised animals during hypoxic exercise (Fig. 1).


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  		Table 1. Data at peak incremental exercise

 

Figure 1
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  		Fig. 1. Ventilation and gas exchange during incremental exercise while breathing 13% O2. At a similar peak O2 uptake, arterial pH (A) and base excess (B) were higher while arterial bicarbonate (C) and lactate concentration (D) were lower in animals raised at high altitude (HA) than at sea level (SL). Values are means ± SD. All were P < 0.05 by repeated-measures ANOVA.

 
During steady-state exercise, log SDV did not change significantly from rest to exercise and the relationships of log SDQ with respect to O2 uptake or ventilation did not differ between groups breathing either 21 or 13% O2 (Fig. 2A). The log SDQ increased significantly from rest to exercise (P < 0.0001), but the relationships of log SDQ with respect to O2 uptake or cardiac output did not differ between groups while breathing either 21 or 13% O2 (Fig. 2B). The physiological dead space did not differ between groups and shunt fraction was negligible (Table 2). In HA-raised animals, arterial O2 saturation during exercise was significantly higher than that in SL-raised control animals while breathing 13% O2 but not while breathing 21% O2 (Fig. 3A). In both groups, the increase in A-aDO2 during exercise attributable to uneven VA/Q distributions (i.e., predicted A-aDO2) was similar while breathing 21 or 13% O2 (Fig. 3B). In HA-raised animals during exercise while breathing 13% O2 compared with SL controls, the measured A-aDO2 with respect to O2 uptake was lower (Fig. 3C), leading to a significantly lower A-aDO2 attributable to diffusion limitation (measured-predicted A-aDO2, P < 0.05, Fig. 3D). The DLO2 estimated during exercise breathing 13% O2 was significantly higher in HA-raised animals than in their SL-raised littermates (Fig. 4).


Figure 2
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  		Fig. 2. The dispersion of the ventilation (log SDV; A) and perfusion (log SDQ; B) distributions during exercise while breathing either 21 or 13% O2 did not differ between HA and SL groups (P > 0.05). Values are means ± SD by analysis of covariance.

 

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  		Table 2. Hemodynamic and inert gas elimination studies at heavy exercise

 

Figure 3
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  		Fig. 3. A: arterial O2 saturation during hypoxic exercise while breathing 13% O2 was significantly higher with respect to O2 uptake in HA-raised animals relative to SL controls (P < 0.05). B: the alveolar-arterial O2 tension gradient (A-aDO2) predicted from the dispersion of ventilation-perfusion (VA/Q) distributions was not different between groups (P > 0.05). C: A-aDO2 measured with respect to O2 uptake while breathing 13% O2 was lower in HA-raised animals (P < 0.05). D: the difference of (measured-predicted) A-aDO2 while breathing 13% O2 was lower in HA-raised animals compared with SL controls (P < 0.05). Values are means ± SD by analysis of covariance.

 

Figure 4
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  		Fig. 4. Lung diffusing capacity for oxygen (DLO2), calculated from the difference between measured and predicted A-aDO2 when breathing 13% O2 was lower at a given cardiac output during exercise in animals raised at HA (P < 0.05 by analysis of covariance). Values are means ± SD.

 
The relationship between mean pulmonary arterial pressure and cardiac output was not different between groups while breathing either 21 or 13% O2 (Fig. 5A). The systemic arterial pressure at a given cardiac output was lower in HA-raised animals during hypoxic exercise, reaching statistical significance while breathing 13% O2 (P < 0.05) and borderline significance while breathing 21% O2 (P < 0.07; Fig. 5B).


Figure 5
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  		Fig. 5. A: mean pulmonary arterial pressure was not different between groups with respect to cardiac output during normoxic or hypoxic exercise. B: mean systemic arterial pressure at a given cardiac output during was lower in animals raised at HA than in controls raised at SL during normoxic (P < 0.07) and hypoxic (P < 0.05) exercise. Values are means ± SD by analysis of covariance.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Summary of findings.   This study examined whether adaptation to 5 mo of HA residence during somatic maturation improves long-term exercise and lung function in adulthood. We anticipated that physiological effects related to heightened erythropoiesis, compartmental fluid shift, hyperventilation, reduced maximal cardiac output (51), pulmonary arterial hypertension, and pulmonary vascular hyperreactivity (20) would regress after reacclimatization to SL, whereas effects related to structural growth or remodeling would be irreversible (31). In these dogs, we reported previously (40) that minute ventilation and hematocrit normalized and cardiac output showed an expected rebound increase 1 mo after return to SL prior to somatic maturity. However, blood volume (including erythrocyte and plasma volumes) as well as DLCO and its components (membrane diffusing capacity and pulmonary capillary blood volume) were significantly elevated 1 mo after return to SL and remained elevated up to 2 years later (40). In the present study using an independent technique, we extended the previous findings by showing that the HA-raised animals exhibited long-term improvement of diffusive O2 transport while breathing a hypoxic gas mixture at SL, associated with improved DLO2, gas exchange efficiency, and arterial O2 saturation as well as lower base excess, peak blood lactate concentration, and lower mean systemic arterial pressure at heavy exercise. Maximal O2 uptake, VA/Q distributions, and pulmonary arterial pressure were unaltered from that in SL-raised littermates. These differences, which have persisted more than 2.5 years after returning to SL, support the interpretation that a relatively short period of HA exposure during somatic maturation permanently enhanced diffusive O2 transport and metabolic efficiency during exercise under hypoxic conditions.

Exercise capacity after HA residence.   Native highlanders demonstrate superior work capacity compared with lowlanders acclimatized to HA; however, differences are not based on a higher maximum aerobic power but rather on a better metabolic economy during exercise at HA. Marconi, Marzorati, and Cerretelli (37) in a recent review reported that peak O2 uptake of Tibetan and Andean natives at HA is not significantly higher than that of Asian or Caucasian lowlanders who chronically reside at 3,400-to-4,700-m altitude. Metabolic adaptations, such as increased muscle myoglobin content and antioxidant defense, are thought to enhance the efficiency of muscle oxidative metabolism, thereby improving submaximal exercise performance in highlanders despite similar peak O2 uptake. Arterial O2 saturation is higher and A-aDO2 lower in Tibetan and Andean HA natives compared with acclimatized lowlanders (7, 56), consistent with improved O2 uptake across the lung. Wagner et al. (52) also found a significantly higher DLO2 in native Bolivian highlanders than in acclimatized Scandinavian lowlanders. Second-generation Tibetans born and living at a low altitude acclimatize more readily to HA than Caucasians independent of fitness (38). Even among Tibetans, those living at 4,400 m achieve better work performance for a given O2 uptake with less cardiorespiratory effort compared with those living at 3,658 m (13), suggesting that both genetic and acquired mechanisms of O2 transport adaptation are invoked in highland natives. In our animals raised at HA for a relatively short time during maturation, there was no long-term improvement of maximal O2 uptake in normoxia or hypoxia but metabolic efficiency and pulmonary gas exchange during hypoxic exercise were improved consistent with the above observations in native highlanders.

Compensation in gas exchange.   While breathing ambient air at SL, alveolar O2 uptake by diffusion is usually not a limiting factor to O2 transport except in highly aerobic animals and elite athletes. However, while breathing a hypoxic gas or during HA exposure, alveolar-capillary O2 diffusion becomes an important limitation to O2 transport. During HA residence, compensatory responses occur aimed at increasing O2 uptake across the blood-gas barrier and minimizing A-aDO2. These compensatory responses include erythropoiesis and vasodilatation as well as growth and/or remodeling of alveolar-capillary network.

During acclimatization to HA, organs that experience high O2 demands, such as skeletal and cardiac muscle, adapt via downregulation of their functional capacities perhaps as a way of minimizing hypoxic tissue injury and maximizing the efficiency of O2 utilization (5, 17, 26). At the same time, two organs involved in O2 uptake, blood and the alveolar-capillary gas exchanger, appear to increase in capacity. HA-induced polycythemia improve O2 transport by increasing O2 carrying capacity of blood and hence convective O2 delivery, and by improving physical interactions between erythrocyte and capillary-tissue membranes and hence diffusive O2 uptake (28). Under basal conditions, alveolar capillary erythrocytes are nonuniformly distributed; capillaries devoid of erythrocyte flow do not participate in gas exchange regardless of the availability of anatomical alveolar-capillary surfaces. Polycythemia, by increasing the number of capillaries perfused with erythrocytes and improving erythrocyte distribution among capillaries at a given cardiac output, allows greater utilization of the anatomical surface for diffusion.

The downside of HA-induced polycythemia is elevated pulmonary and systemic vascular resistance, the cause of adverse effects from blood-doping in elite athletes. The adverse effects can be minimized by splenic sequestration of the extra erythrocytes and/or structural enlargement of the microvascular bed. In aerobic species including the dog, horse, and seal, a large spleen stores up to 30% of total body erythrocytes and about 10% of total body blood volume at a hematocrit of 80–90% (2, 3, 10, 21). Upon exercise or hypoxic exposure, sympathetic stimulation causes splenic contraction and releases the sequestered erythrocytes (50), leading to reversible increases in circulating blood volume and hematocrit as well as enhancement of convective and diffusive O2 transport. Because splenic autotransfusion occurs reversibly and only during periods of heightened O2 demand accompanied by maximal vasodilatory responses, resting hematocrit and blood volume remain normal and pulmonary and systemic arterial hypertension do not develop. Splenectomy in Thoroughbred horses and dogs eliminates exercise-induced polycythemia and impairs convective and diffusive O2 transport in the lung and the periphery (14, 53). In hypoxic rats, the spleen-to-body weight ratio and splenic iron uptake are increased (42, 49). Therefore, dynamic splenic sequestration and release of erythrocytes in the dog is one potential mechanism for accommodating HA-induced erythropoiesis without incurring adverse systemic effects. In our dogs the wet and dry spleen weights measured postmortem were slightly but not significantly higher in HA-raised animals (40). The effect of HA exposure on splenic histology remains to be examined.

Chronic hypoxic exposure has been associated with an increased capillary density in the brain (33), myocardium (43), and skeletal muscle (39). The higher muscle capillary density after hypoxia exposure has been attributed to downsizing of nonvascular tissue rather than new growth of capillaries (25). The effect of HA residence on alveolar capillary structure is unknown; we plan to examine this issue in these animals.

Our hemodynamic results are consistent with that reported by Grover et al. (20) in beagle puppies raised at 3,100 m altitude for 14 mo where HA-induced pulmonary arterial hypertension was completely reversed 8 mo after return to SL; systemic arterial pressure was not measured. Airway NO output is higher in Tibetan natives than in lowlanders, associated with a higher pulmonary blood flow but a normal pulmonary artery systolic pressure (24). Inhibition of endogenous NO synthase causes a greater increase in pulmonary vascular resistance in Tibetan sheep native to 3,750 m than in low-altitude sheep (34). These findings suggest an augmented respiratory NO production during HA adaptation allows a higher pulmonary blood flow and O2 delivery to compensate for ambient hypoxia without incurring greater pulmonary arterial hypertension. Augmented endogenous NO production may have contributed to the lower systemic arterial blood pressure and the lack of persistent pulmonary arterial hypertension in our animals raised at HA.

We conclude that in actively growing animals, a relatively short period of HA residence that was discontinued prior to somatic maturation permanently enhanced pulmonary gas exchange, hemodynamic function, and metabolic efficiency of exercise. Long-term functional enhancement is associated with an elevated blood volume even after systemic hematocrit had normalized (40). Exercise training may have helped maintain the HA-induced responses and prevented their regression after animals return to SL.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This research was supported by National Heart, Lung, and Blood Institute Grants R01 HL-045716, HL-040070, HL-054060, and HL-062873. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute or of the National Institutes of Health.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank Dr. Frank L. Powell, Dr. Phil Richter, and the staff of the University of California White Mountain Research Station for assistance with animal transport and care that made this study possible. We also thank the staff of the Animal Resources Center at the University of Texas Southwestern Medical Center for veterinary assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. L. Johnson, Jr., Dept. of Internal Medicine, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9034

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


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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