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J Appl Physiol 103: 1496-1505, 2007. First published August 2, 2007; doi:10.1152/japplphysiol.00281.2007
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The canine spleen in oxygen transport: gas exchange and hemodynamic responses to splenectomy

Connie C. W. Hsia,1 Robert L. Johnson, Jr.,1 D. Merrill Dane,1 Eugene Y. Wu,1 Aaron S. Estrera,2 Harrieth E. Wagner,3 and Peter D. Wagner3

Departments of 1Internal Medicine and 2Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas; 3Department of Medicine, University of California, San Diego, La Jolla, California

Submitted 12 March 2007 ; accepted in final form 27 July 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
In athletic animals the spleen induces acute polycythemia by dynamic contraction that releases red blood cells into the circulation in response to increased O2 demand and metabolic stress; when energy demand is relieved, the polycythemia is rapidly reversed by splenic relaxation. We have shown in adult foxhounds that splenectomy eliminates exercise-induced polycythemia, thereby reducing peak O2 uptake and lung diffusing capacity for carbon monoxide (DLCO) as well as exaggerating preexisting DLCO impairment imposed by pneumonectomy (Dane DM, Hsia CC, Wu EY, Hogg RT, Hogg DC, Estrera AS, Johnson RL Jr. J Appl Physiol 101: 289–297, 2006). To examine whether the postsplenectomy reduction in DLCO leads to abnormalities in O2 diffusion, ventilation-perfusion inequality, or hemodynamic function, we studied these animals via the multiple inert gas elimination technique at rest and during exercise at a constant workload equivalent to 50% or 80% of peak O2 uptake while breathing 21% and 14% O2 in balanced order. From rest to exercise after splenectomy, minute ventilation was significantly elevated with respect to O2 uptake compared with exercise before splenectomy; cardiac output, O2 delivery, and mean pulmonary and systemic arterial blood pressures were 10–20% lower, while O2 extraction was elevated with respect to O2 uptake. Ventilation-perfusion inequality was unchanged, but O2 diffusing capacities of lung (DLO2) and peripheral tissue during exercise were lower with respect to cardiac output postsplenectomy by 32% and 25%, respectively. The relationship between DLO2 and DLCO was unchanged by splenectomy. We conclude that the canine spleen regulates both convective and diffusive O2 transport during exercise to increase maximal O2 uptake.

ventilation-perfusion distributions; hemodynamic function; alveolar-arterial oxygen tension gradient; diffusing capacity for oxygen; convective oxygen delivery; pneumonectomy; dog

VERTEBRATE SPECIES with a high oxygen demand, ranging from rainbow trout (11) to dogs (24), horses (57), and diving mammals (29), respond to the stress of exercise by graded splenic contraction, a function first described by Joseph Barcroft and colleagues (3, 4). Splenic contraction releases blood at a hematocrit of 80–90% into the circulation, thereby increasing circulating hematocrit, blood and red cell volumes and O2 carrying capacity above resting levels (7). Once the animal stops exercise, the process is reversed, and blood is sequestered back into the spleen. This form of reversible autologous blood transfusion has the advantage of augmenting O2 uptake selectively during periods of high metabolic demand without the deleterious effects of chronically elevated circulating hematocrit, blood volume, or blood viscosity that are associated with blood doping in human athletes (35) or primary or secondary polycythemia caused by pathologic conditions (59).

Splenectomy has been shown in canines to limit exercise capacity, cardiac output, and peak O2 uptake through its influence on circulating hematocrit and O2 delivery (38, 54). To understand how dynamic autologous blood infusion by splenic contraction regulates diffusive as well as convective O2 transport, we studied trained adult foxhounds before and after splenectomy (7) and reported that, following splenectomy, circulating blood or red cell volume was not altered at rest, but exercise-induced polycythemia was eliminated. Peak O2 uptake was reduced by 30% after splenectomy, as were lung diffusing capacity for carbon monoxide (DLCO) and its recruitment during exercise, measured by a noninvasive rebreathing technique (7). In addition, splenectomy exaggerated the existing reduction of DLCO imposed by pneumonectomy (7). In the present study, we utilized the multiple inert gas elimination technique to examine the hypothesis that splenectomy impairs additional components of O2 transport in the lung (7). We directly addressed: 1) whether a reduced DLCO postsplenectomy corresponds to a higher alveolar-arterial O2 tension gradient (A-aDO2) and lower O2 diffusing capacity in the lung (DLO2); 2) whether altered diffusive O2 transport in the lung is associated with parallel changes in diffusing capacity of peripheral tissue (DTO2), and 3) whether splenectomy alters ventilation-perfusion (VA/Q) relationships, convective O2 delivery, and hemodynamic function during exercise.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Animals.   The Institutional Animal Care and Use Committee approved all protocols and procedures. Six purpose-bred adult male foxhounds were studied at rest and during exercise before and 7–10 mo following splenectomy. Two to three years prior to the present study and as part of a separate project, two animals had undergone right pneumonectomy, and four animals had undergone right thoracotomy without lung resection (SHAM) by established procedures (50). In addition, all animals had bilateral carotid artery loops constructed to permit acute catheterization without the complications of chronic indwelling vascular catheters. The animals were trained to run on a motorized treadmill wearing a sealed respiratory mask for measuring ventilation and gas exchange during exercise (1, 24). Peak O2 uptake, lung volume, pulmonary blood flow, DLCO and its components membrane diffusing capacity (DMCO) and pulmonary capillary blood volume (Vc), as well as blood, red cell, and plasma volumes were measured before and 4–9 mo after splenectomy; these results have been reported elsewhere (7). The present invasive studies were performed before and 9 mo after splenectomy.

Apparatus.   The leak-free respiratory mask was customized to each animal, sealed around the muzzle with a modified latex glove and duct tape, and connected to a two-way valve (Model 2700, Hans Rudolph, Kansas City, MO). The inspiratory port was either open to room air or connected to a meteorological balloon containing 14% O2. Inspired and expired ventilation was measured by separate heated screen pneumotachometers (Model 3813, Hans Rudolph), and expired gas concentrations were continuously sampled by a mass spectrometer (MGA 1100, Perkin-Elmer, Waltham, MA) distal to a mixing chamber. To ensure accurate gas concentrations, expiratory tubing was also heated. The pneumotachometer-computer system was calibrated on the day of study. Minute ventilation, O2 uptake, CO2 production, and respiratory rate were followed breath-by-breath and averaged over 5 or 10 breaths. Heart rate and rectal temperature were continuously recorded. Pulmonary and systemic vascular pressures were recorded with identical fluid-filled transducers (P23 ID, Statham Instruments) via Hewlett Packard carrier amplifiers and digitized. Pressure transducers were calibrated with a mercury manometer on the day of study. All signals were digitized at 50 Hz.

Hemodynamic measurements.   On the day of study and with the animal standing in a sling, a 5 French 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 French 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 (see 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.

Multiple inert gas elimination technique.   As previously described, (26, 28, 58), 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 about 1/4000th of the dog's minute ventilation to ensure an adequate signal-to-noise ratio. At rest, the infusion began 20 min before sampling. Upon exercise, inert gas exchange at the blood-gas interface reaches equilibrium rapidly; therefore, sampling was performed after 3 min of infusion. 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.

Blood measurements.   At each workload, arterial and mixed venous blood was sampled and analyzed for conventional blood gases (ABL-500, Radiometer, Copenhagen, Denmark), O2 content, hemoglobin (OSM3, Radiometer), and lactate (YSI, Yellow Springs, OH) concentrations. Hematocrit was measured by microcapillary centrifuge. The measured PO2, PCO2, and pH were adjusted to the simultaneously measured blood temperature (33). Cardiac output was determined by the Direct Fick method from measured O2 uptake and arterial and mixed venous PO2 and O2 saturation. O2 delivery was calculated as the product of arterial O2 content and cardiac output. Mean tissue capillary PO2 and DTO2 were calculated by means of a numerical integration procedure (55).

Protocol.   Each dog underwent two exercise protocols, one while breathing room air and one while breathing 14% O2, in balanced order. Baseline measurements were made with the animal standing on the treadmill and breathing the selected inspired O2 concentration. After 5 min of warm-up exercise (6 mph, 0% grade), the speed and incline were increased quickly to a predetermined level equivalent to either 50 or 80% of the animal's previously measured peak O2 uptake and sustained for about 4–5 min. Relative exercise intensities were used to ensure that each animal achieved the highest work output that it could sustain for the duration necessary to obtain all the measurements under each ambient O2 concentration. By the end of the third minute at a given workload, when O2 uptake and ventilation generally reached a near-plateau, 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 concentrations 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. After collecting the above samples, additional duplicate arterial and mixed venous blood samples (2 ml each) were drawn for blood gas measurements. After sample collection, the animal walked slowly on the treadmill at 4 mph and 0% grade for 10 min to cool down, followed by rest between exercise periods until heart rate, respiratory rate, and ventilation returned to baseline.

Data analysis.   Results were normalized by body weight and reported as mean ± SD. Pre- to postsplenectomy values were compared by paired t-test with each animal as its own control. The dispersion of 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 combined data (inert gas concentrations, cardiac output, ventilation, hemoglobin concentration, blood temperature, base excess, barometric pressure, inspired PO2 and PCO2, mixed venous PO2 and PCO2), we determined the arterial PO2 (PaO2), arterial PCO2 (PaCO2) and the alveolar-arterial O2 tension difference (A-aDO2) attributable to VA/Q inhomogeneity assuming complete alveolar-capillary diffusion equilibrium (i.e., predicted A-aDO2) (52). The measured A-aDO2 was estimated from PaO2 and the ideal alveolar PO2. When the measured A-aDO2 exceeds that predicted from VA/Q inhomogeneity alone, the difference was attributed to a combination of alveolar-end capillary diffusion impairment and postpulmonary shunting.

Ventilation-perfusion relationships were measured at two inspired O2 tensions to assess the relative magnitude of VA/Q mismatch and diffusion impairment. 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 14% O2 has the opposite effect (36). Differences in response 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 negligible diffusion-perfusion (DLO2/Q) inhomogeneity, an estimate of the whole lung DLO2 that accounts for the difference between measured and predicted A-aDO2 during hypoxic exercise was obtained by means of established algorithms (17). This estimate of DLO2 is the smallest value that can account for the data. Assuming negligible tissue PO2, the pressure gradient driving O2 uptake from capillary to tissue is the mean capillary PO2, and the diffusing capacity of tissue (DTO2 in ml·min–1·mmHg–1·kg–1) could be estimated from the slope of the relationship between O2 uptake and mean tissue capillary PO2 at heavy exercise while breathing 21% and 14% O2. This estimation assumes homogenous tissue blood flow with respect to tissue O2 uptake without shunting of O2, and that all of the residual O2 returning in the mixed venous blood reflects diffusion limitation in tissue. These assumptions have been discussed extensively elsewhere (20, 21, 44, 46, 56).

Ventilatory, gas exchange, hemodynamic, and VA/Q indices, as well as DLO2, were plotted as a function of minute ventilation, O2 uptake, and/or cardiac output, and the relationships between pre- and postsplenectomy values were statistically compared by analysis of covariance (StatView v.5.0, SAS Institute, Cary, NC). Since we already knew that DLCO was reduced postsplenectomy (7), and our objective was to determine if O2 diffusing capacity was correspondingly reduced, a one-tailed distribution was assumed in the statistical comparisons of measured vs. predicted A-aDO2, DLO2, and DTO2. A two-tailed distribution was assumed for all other parameters. P ≤ 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
In Table 1 we compare measurements obtained at rest and peak exercise pre- and postsplenectomy with paired statistical analysis, using each animal as its own control. These results have been reported previously (7). Body weight was not different between pre- and postsplenectomy states. Resting hematocrit (43.4%) in these unsedated presplenectomy animals was similar to that previously reported by us in conscious unsedated foxhounds (25). Both resting hematocrit and red cell volume (46.3 ml/kg) in unsedated presplenectomy animals were higher than that reported in sedated or anesthetized adult dogs (average hematocrit 37.2–39.8%; average red cell volume 29.3–34.2 ml/kg) (13, 31). Plasma volume, measured by Evans Blue dye dilution, declined ~6% from rest to 50% of maximal O2 uptake postsplenectomy (7). As the measured change in plasma volume was small and we could not directly measure plasma volume at peak exercise, for practical purposes we assumed a constant plasma volume. Red cell volume at peak exercise was estimated from the change in hematocrit, which increased by an average of 20% from rest to exercise presplenectomy and did not change postsplenectomy (7). The hematological response to splenectomy was similar between SHAM and pneumonectomized animals (7).


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  		Table 1. Hematologic data and oxygen uptake

 
Data obtained during exercise at the highest constant workload are shown in Tables 2 and 3 (breathing 21% and 14% O2, respectively). Since postpneumonectomy animals achieved significantly lower maximal O2 uptake than SHAM animals, we summarized their data separately. Since the response to splenectomy was similar in SHAM and postpneumonectomy animals in the present study as in the previously reported study (7), combined data from all animals are shown in the figures at three work levels (rest, and exercise at 50% and 80% of peak O2 uptake) with respect to O2 uptake or cardiac output. During the period of measurement of blood and inert gases, ventilatory, gas exchange, and hemodynamic parameters remained relatively constant, as shown by continuous recording of ventilatory and gas exchange data as well as duplicate blood and expired gas samples.


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  		Table 2. Measurements during heavy exercise while breathing 21% O2

 

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  		Table 3. Measurements during heavy exercise while breathing 14% O2

 
While breathing 21% or 14% O2 during exercise, minute ventilation was higher and cardiac output and O2 delivery were lower, while O2 extraction at a given O2 uptake was higher postsplenectomy compared with presplenectomy (Fig. 1). While breathing 21% or 14% O2, the relationships of mean pulmonary arterial and mean systemic arterial pressures with respect to O2 uptake were significantly lower postsplenectomy than presplenectomy (Fig. 2). The relationships of arterial PO2, PCO2, and pH with respect to O2 uptake were not significantly different pre- and postsplenectomy, breathing either 21% or 14% O2 (Fig. 3). The dispersion of VA/Q distributions indexed by log SDQ and log SDV with respect to O2 uptake during exercise was not significantly altered by splenectomy (Fig. 4), although log SDV at rest was highly variable due to a variable ventilatory pattern. The A-aDO2 predicted from VA/Q distributions was lower or unchanged with respect to O2 uptake while breathing 21% and 14% O2, respectively, postsplenectomy compared with presplenectomy (Fig. 5, top). The measured A-aDO2 was significantly higher postsplenectomy compared with presplenectomy with respect to O2 uptake while breathing 14% O2, but not while breathing 21% O2 (Fig. 5, middle). The difference between measured and predicted A-aDO2 with respect to O2 uptake that could be attributed to diffusion limitation and postpulmonary shunting was slightly but not significantly greater postsplenectomy at either inspired O2 levels (Fig. 5, bottom). However, the estimated DLO2 with respect to cardiac output during exercise was up to 32% lower postsplenectomy compared with presplenectomy (Fig. 6). Shunt fraction was negligible (<1%) under all conditions. The slope of the line through the origin between O2 uptake and mean tissue capillary PO2 measured at the heaviest exercise intensity while breathing 21% and 14% O2 provides an estimate of DTO2, which was ~25% lower postsplenectomy compared with presplenectomy (Fig. 7).


Figure 1
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  		Fig. 1. Minute ventilation (top row) was significantly higher, cardiac output (second row) and O2 delivery (third row) were significantly lower, and O2 extraction (bottom row) was significantly increased at a given O2 uptake while breathing 21% (left) or 14% (right) O2 postsplenectomy compared with presplenectomy. Mean ± SD, *P < 0.05 pre- vs. postsplenectomy by analysis of covariance.

 

Figure 2
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  		Fig. 2. Mean systemic (top) and mean pulmonary (bottom) arterial pressures were reduced postsplenectomy compared with presplenectomy at rest and during exercise while breathing 21% (left) or 14% O2 (right). Mean ± SD, *P < 0.05 pre- vs. postsplenectomy by analysis of covariance.

 

Figure 3
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  		Fig. 3. The relationships of arterial PO2 (top), arterial PCO2 (middle) and arterial pH (bottom) with respect to O2 uptake were not significantly different from pre- to postsplenectomy while breathing 21% (left) or 14% O2 (right). Mean ± SD.

 

Figure 4
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  		Fig. 4. Top: Log SDV was lower at rest postsplenectomy while breathing 21% O2 compared with presplenectomy. During exercise log SDV at a given ventilation was not significantly different pre- and postsplenectomy breathing 21% (left) or 14% (right) O2. Bottom: At a given cardiac output log SDQ was not significantly different between pre- and postsplenectomy states. Mean ± SD, *P < 0.05 pre- vs. postsplenectomy by analysis of covariance.

 

Figure 5
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  		Fig. 5. Top: The alveolar-arterial O2 tension gradient (A-aDO2) predicted from VA/Q distributions during exercise was lower postsplenectomy compared with presplenectomy while breathing 21% O2 (left) but not while breathing 14% O2 (right). Middle: The measured A-aDO2 was significantly higher during exercise postsplenectomy while breathing 14% but not 21% O2. Bottom: The difference between measured and predicted A-aDO2 was slightly but not significantly higher during exercise while breathing either 21% or 14% O2. Mean ± SD, *P < 0.05 pre- vs. postsplenectomy by analysis of covariance.

 

Figure 6
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  		Fig. 6. Postsplenectomy, lung diffusing capacity for O2 (DLO2) measured at a given cardiac output during exercise while breathing 14% O2 was lower compared with presplenectomy, and exhibited no recruitment from rest to exercise. Mean ± SD, P < 0.005 by analysis of covariance.

 

Figure 7
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  		Fig. 7. The O2 diffusing capacity of peripheral tissue (DTO2, ml·min–1·Torr–1·kg–1), estimated from the slope of O2 uptake with respect to mean tissue capillary PO2 measured at the highest constant exercise workload while breathing 21% or 14% O2, was significantly lower post- compared with presplenectomy. For pooled data from all animals, r2 of the regression line through the origin is 0.88 presplenectomy and 0.99 postsplenectomy. Mean ± SD, P < 0.05 by paired t-test.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
This report is the second component in this series of studies. In the first report (7), we showed that splenectomy in adult foxhounds impairs maximal O2 uptake as well as lung and membrane diffusing capacity for carbon monoxide at rest and during exercise. The present study used an independent method in the same animals to demonstrate directly that splenectomy impairs pulmonary O2 exchange without affecting VA/Q distributions. After splenectomy there was little recruitment of DLO2 from rest to exercise, consistent with the impairment in DLCO recruitment previously reported in these animals (7). The reduction in lung diffusing capacity parallels a similar magnitude of reduction in peripheral tissue diffusing capacity. Convective O2 delivery was reduced postsplenectomy because of a lower cardiac output, likely the result of a reduced cardiac preload, coupled with the lack of exercise-induced increase in circulating hematocrit (Table 1) (7). Owing to the lack of exercise-induced polycythemia, mean pulmonary and systemic arterial blood pressures at a given exercise intensity were lower following splenectomy compared with before. These results show that splenic contraction significantly augments convective as well as diffusive O2 transport via multiple mechanisms, but also exaggerates systemic and pulmonary vascular pressures during exercise.

Several significant conclusions arise from this study. First, the spleen is clearly an organ that augments O2 transport in highly athletic species. In seals, horses, and dogs (5, 14, 29, 51), the spleen sequesters 30–50% of total red cell volume or 13% of blood volume at a hematocrit of 85–90%. Splenic contraction releases red cells into the circulation during exercise, accounting for a 13–30% increase in maximal O2 uptake; the higher the presplenectomy maximal O2 uptake, the greater the impairment following splenectomy (7, 38, 54, 57). In sedentary species, the spleen is smaller relative to body weight. However, even the human spleen, reported to contain 85–250 ml of packed red blood cells or ~8% of total body red blood cell volume (2, 48, 49), contracts by 60–80% in volume at maximal exercise or during breath-hold (2, 34, 49); this amount is potentially equivalent to the infusion of one unit of whole blood. It has been shown that exercise training increases total blood volume (47), and blood volume is higher in endurance athletes than in untrained subjects (16). It remains to be determined whether part of the increased blood volume is stored in the spleen and whether elite athletes possess a larger splenic blood-storing capacity than sedentary subjects.

Second, splenic contraction enhances both diffusive and convective O2 transport. Convective O2 delivery at exercise is impaired postsplenectomy because of a lower O2 content as well as a lower cardiac output; the latter is likely the result of a reduced preload due to the elimination of exercise-induced increase in blood volume. The cause of a lower diffusing capacity postsplenectomy has been discussed extensively in our first paper (7). From DLCO measured at two alveolar O2 tensions, the membrane and blood components of diffusing capacity were partitioned by the Roughton-Forster technique (45). We observed that the reduction in postsplenectomy DLCO with respect to pulmonary blood flow was primarily due to a lower membrane diffusing capacity, while pulmonary capillary blood volume changed variably (7). However, membrane diffusing capacity estimated by this technique does not index anatomical capillary surface per se, but rather represents the net resistance resulting from dynamic interactions between red cell and tissue membranes. Our laboratory has simulated O2 and CO fluxes across the alveolar air-tissue-blood barrier (10, 23, 27) and showed that increasing the number and/or uniformity of red cells within and among alveolar capillaries brings more of the available red cell membrane surface into close proximity with capillary tissue surfaces, thereby facilitating O2 and CO transfer. An increased circulating blood volume due to splenic contraction would accentuate end-diastolic ventricular filling and stroke volume via the Starling mechanism (53), which in turn enhances pulmonary capillary recruitment as well as more uniform distribution of red cell transit times (41, 42). A higher capillary hematocrit induced by splenic contraction also enhances physical interactions between capillary and red cell surfaces at a constant level of recruitment, leading to augmentation of membrane diffusing capacity (23). After splenectomy, cardiac output is reduced with respect to O2 uptake, and the exercise-induced rise in hematocrit is eliminated. Thus, the postsplenectomy reduction in convective O2 transport contributes to the loss of capillary-red cell membrane interactions, resulting in impaired recruitment and concurrent reductions of DLO2 and DTO2; the latter has also been reported in splenectomized thoroughbred horses (57).

Assuming homogeneous distribution of perfusion (Q) with respect to diffusion (D), muscle O2 extraction has been expressed as an exponential function of the ratio D/βQ, where β is the capacitance of blood represented by the slope of the oxyhemoglobin dissociation curve and is directly proportional to hemoglobin concentration (40). Splenectomy decreases the terms Q and β at exercise, which increases fractional O2 extraction. The lower Q and β in turn impairs capillary-red cell membrane interactions, reduces D, and offsets the increase in fractional O2 extraction (see above). Independent of these factors, blood flow becomes more heterogeneous in hard working muscles, causing D/Q mismatch, which further reduces efficiency of O2 transfer and may constitute a significant factor that limits maximal O2 uptake (18, 19, 40). Our estimation of DTO2 was based on the assumption of homogeneity and represents a lower limit of the true peripheral O2 conductance. An increase in peripheral blood flow heterogeneity postsplenectomy could also have contributed to the reduction in DTO2. The remaining possibility, that splenectomy stimulated capillary remodeling and caused a reduction in DTO2, cannot be addressed from these physiologic data.

Besides increasing overall resistance to O2 transport, splenectomy alters the distribution of resistance among the component steps. We estimated the lumped parameter resistances to O2 transport ({Delta}PO2/{Delta}VO2) pre- and postsplenectomy while breathing 14% O2 at the workload equivalent to a total body O2 uptake of ~50 ml·min–1·kg–1, i.e., the highest level reached during constant workload exercise postsplenectomy. The drops in O2 partial pressure imposed by ventilation (inspired-to-alveolar PO2), alveolar VA/Q inequality and diffusion limitation (A-aDO2), and peripheral extraction (arterial-to-mixed venous PO2) were divided by O2 uptake, and the resulting resistance terms were expressed as percentages of total resistance (Fig. 8). After splenectomy, alveolar gas transfer and peripheral O2 extraction constituted larger percentages of overall resistance compared with before, while the contribution from ventilation was lower.


Figure 8
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  		Fig. 8. Distribution of serial lumped parameter resistances to O2 transport imposed by ventilation, alveolar gas transfer (VA/Q inequality and diffusion), and peripheral perfusion and extraction were compared pre- and postsplenectomy at an O2 uptake of 50 ml·min–1·kg–1 while breathing 14% O2. The relative resistances to O2 transport in the alveoli and periphery, expressed as percentages of the total resistance, were increased following splenectomy. Mean ± SD. *P < 0.05 vs. presplenectomy by paired t-test.

 
Third, canine splenic contraction contributes significantly to postpneumonectomy compensation in O2 transport. We found previously that SHAM and pneumonectomized animals exhibited a similar magnitude of impairment in DLCO and DMCO postsplenectomy (7); similar responses were also observed for the parameters measured in the present study. Peak O2 uptake in pneumonectomized animals (95 and 71 ml·min–1·kg–1 pre- and postsplenectomy, respectively) remained high compared with trained human subjects, and the magnitude of splenectomy-induced reduction in peak O2 uptake (25–30%) was similar to that in control (SHAM) animals. After splenectomy, hematocrit at peak exercise, O2 delivery, and DLO2 were reduced by a similar degree in both groups. Before splenectomy, DLO2 at heavy exercise in pneumonectomized animals was about 40% lower than normal. Splenectomy further exaggerated diffusion limitation imposed by prior lung resection, so that their postsplenectomy DLO2 at heavy exercise was 65% below the presplenectomy values in a normal animal. Therefore, splenic contraction provided significant compensation by protecting O2 transport in the presence of diminished pulmonary reserves.

Fourth, the downside of elevated circulating blood volume and hematocrit caused by splenic contraction is the associated increase in blood viscosity and vascular resistance, evidenced in our animals by the higher vascular pressures before splenectomy. Excessive chronic polycythemia is known to compromise cerebral blood flow and increase the risks of ischemia and thrombosis (15, 59). These adverse risks are related to both a higher blood viscosity as well as a lower cardiac output as O2 content increases; the latter response maintains a constant O2 delivery over a wide range of O2 content (37). The arterial hypertension associated with splenic contraction may also have been elicited via reflex or local neuroendocrine responses. In native highlanders excessive chronic polycythemia impairs pulmonary gas exchange efficiency (6, 39), while in the normal animal at sea level hemodilution improves gas exchange and the homogeneity of perfusion distribution in both lung and muscle (8, 30). In contrast to the chronic polycythemia associated with high altitude exposure or hematological and pulmonary diseases, polycythemia in the exercising dog develops only for the duration of heightened O2 demand when vasoregulatory mechanisms have already minimized systemic and pulmonary vascular resistances, and the elevation in vascular resistance is fully reversible when O2 demand returns to normal. Thus, the splenic reservoir is an important evolutionary feature that enhances survival and adaptation of athletic animals by maximizing their aerobic capacity and endurance while minimizing the risks of polycythemia-associated complications. In comparison, blood boosting by autologous red cell transfusion or doping with recombinant erythropoietin in human athletes generally increases blood and red cell volumes by 10–13% (12, 35), associated with corresponding increases in maximal O2 uptake (9) as well as improvement in endurance, lactate threshold, and heat tolerance (35). Although the fractional increase in red cell volume caused by blood doping or transfusion in athletes is considerably less than that caused by canine splenic contraction, the sustained nature of doping-induced polycythemia lasting for weeks to months potentially increases the risks of hyperviscosity-related adverse events.

The fifth point from these data is the demonstration of direct correspondence between DLCO and DLO2 measured during exercise by two independent methods under different experimental conditions (Fig. 9). Up to now these two methods have been correlated only indirectly (32). DLO2 was estimated from blood and exhaled concentrations of multiple gases under ambient hypoxia. DLCO was measured from exhaled CO concentrations under ambient normoxia and hyperoxia and partitioned into its two components, DMCO and Vc, by standard methods. For a given DLO2 measurement in the present study, the corresponding DLCO value at the same cardiac output was estimated from the relationship between DLCO and cardiac output measured for each animal by the rebreathing technique (7). This comparison shows a significant correlation between DLO2 and DLCO before and after splenectomy, with a slope of 1.7 presplenectomy and 1.6 postsplenectomy.


Figure 9
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  		Fig. 9. The relationship between DLO2 and DLCO was unchanged by splenectomy. DLO2 was measured by the multiple inert gas elimination technique. DLCO at the same cardiac output was estimated from the relationship previously measured using a rebreathing method pre- and postsplenectomy (7). Presplenectomy DLO2 = 1.66DLCO + 0.03, r2 = 0.79. Postsplenectomy DLO2 = 1.57DLCO + 0.04, r2 = 0.59.

 
We conclude that the spleen is a major source for augmentation of O2 transport in athletic animals. Demand-driven splenic contraction during exercise enhances convective and diffusive O2 transport in parallel without significantly altering VA/Q distributions. At a given exercise level, splenic contraction increases pulmonary and systemic vascular pressures; fortunately, the risk of polycythemia-associated complications is minimized by the transient and reversible nature of the red cell infusion and the concurrent vasodilatory response during exercise. Splenic contraction is also a source for compensation in O2 transport under pathologic conditions of diminished O2 supply, i.e., pneumonectomy. During experimental shock, the canine spleen is thought to contract and help maintain cardiac function (22, 43), but little is reported about the underlying mechanisms or its effects on gas exchange. Whether splenic contraction contributes to O2 transport in nonathletic mammals under pathological conditions of diminished O2 supply or increased O2 demand remains to be determined.


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 ABSTRACT
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 DISCUSSION
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ACKNOWLEDGMENTS
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This research was supported by National Institutes of Health grants R01 HL045716, HL040070, HL054060, and HL062873. 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
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
The authors thank Deborah C. Hogg and Richard T. Hogg for assistance with exercise training and testing, and the staff of the Animal Resources Center at the University of Texas Southwestern Medical Center for veterinary care and assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Robert L. Johnson, Jr., Dept. of Internal Medicine, Pulmonary and Critical Care 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.


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 REFERENCES
 

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