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J Appl Physiol 96: 1349-1356, 2004. First published December 12, 2003; doi:10.1152/japplphysiol.01083.2003
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NaHCO3 does not affect arterial O2 tension but attenuates desaturation of hemoglobin in maximally exercising Thoroughbreds

Murli Manohar, Thomas E. Goetz, and Aslam S. Hassan

Departments of Veterinary Biosciences and Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Submitted 6 October 2003 ; accepted in final form 26 November 2003


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The objective of the present study was to examine the effects of preexercise NaHCO3 administration to induce metabolic alkalosis on the arterial oxygenation in racehorses performing maximal exercise. Two sets of experiments, intravenous physiological saline and NaHCO3 (250 mg/kg iv), were carried out on 13 healthy, sound Thoroughbred horses in random order, 7 days apart. Blood-gas variables were examined at rest and during incremental exercise, leading to 120 s of galloping at 14 m/s on a 3.5% uphill grade, which elicited maximal heart rate and induced pulmonary hemorrhage in all horses in both treatments. NaHCO3 administration caused alkalosis and hemodilution in standing horses, but arterial O2 tension and hemoglobin-O2 saturation were unaffected. Thus NaHCO3 administration caused a reduction in arterial O2 content at rest, although the arterial-to-mixed venous blood O2 content gradient was unaffected. During maximal exercise in both treatments, arterial hypoxemia, desaturation, hypercapnia, acidosis, hyperthermia, and hemoconcentration developed. Although the extent of exercise-induced arterial hypoxemia was similar, there was an attenuation of the desaturation of arterial hemoglobin in the NaHCO3-treated horses, which had higher arterial pH. Despite these observations, the arterial blood O2 content of exercising horses was less in the NaHCO3 experiments because of the hemodilution, and an attenuation of the exercise-induced expansion of the arterial-to-mixed venous blood O2 content gradient was observed. It was concluded that preexercise NaHCO3 administration does not affect the development and/or severity of arterial hypoxemia in Thoroughbreds performing short-term, high-intensity exercise.

exercise-induced arterial hypoxemia; blood-gas tensions; metabolic alkalosis; hemoglobin-O2 saturation; arterial desaturation during exercise

SIMILAR TO HUMAN ATHLETES (5, 31), strenuously exercising Thoroughbred horses routinely experience arterial hypoxemia and desaturation of hemoglobin, which limit performance (19). Metabolic acidosis is also observed in strenuously exercising racehorses as blood lactate concentration increases dramatically (19). To mitigate the adverse effects of acidosis and gain a putative ergogenic effect, racehorses are frequently premedicated with NaHCO3. However, despite considerable investigation (1, 6, 8-10, 12, 15, 17, 18, 20, 21, 33), consensus does not exist regarding the beneficial ergogenic effects of NaHCO3 premedication in racehorses. Previous studies have largely been focused on changes in the jugular venous blood acid-base status during and postexercise (6, 8-10, 12, 17, 18, 21, 33), although muscle enzymes, substrates, and metabolites have also been studied (8, 9, 15, 33). There has been one report in Thoroughbred horses, wherein arterial blood-gas tensions were examined during strenuous exercise performed after NaHCO3 administration (20). In this report (20), NaHCO3 administration markedly exaggerated the exercise-induced arterial hypoxemia; mean arterial O2 tension during exercise performed at 80 and 110% of the maximal whole body O2 uptake (O2 max) in the NaHCO3 experiments was 11.1 and 9.2 Torr, respectively, lower than that in the saline-treated horses (20). However, effects of an NaHCO3-induced accentuation of the exercise-induced arterial hypoxemia on the hemoglobin-O2 saturation were not examined. Furthermore, horses premedicated with NaHCO3 had significantly lower arterial O2 tension, even during exercise performed at 40 and 60% O2 max (20), which, in healthy, unmedicated Thoroughbred horses, is not attended by changes in arterial O2 tension (19, 23-27). These observations in exercising horses premedicated with NaHCO3 (20) are in contrast with findings in human subjects, in whom exercise-induced arterial hypoxemia is largely unaffected by preexercise administration of NaHCO3, but the associated alkalosis helps limit the desaturation of arterial hemoglobin (28). Because an exaggeration of the exercise-induced arterial hypoxemia following NaHCO3 administration to horses (20) may adversely affect O2 supply and, in turn, performance (5, 19), the objective of the present study was to reevaluate the effects of preexercise NaHCO3 administration on the arterial oxygenation in Thoroughbred horses performing short-term, high-intensity exercise.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Horses. Experiments were carried out on 13 healthy, sound Thoroughbred horses (5 fillies, 8 geldings), 3-6 yr old, and weighing 450 ± 23 kg. They were housed in an air-conditioned building and were accustomed to being handled by people. The horses were maintained on alfalfa hay and oats with free access to water. The horses were dewormed periodically and were inoculated with tetanus toxoid and strangles vaccine. Our protocols and procedures were approved by the Institutional Animal Care and Use Committees.

Exercise training and work intensity eliciting maximal heart rate. After initial familiarization with walking, trotting, cantering, and galloping on the high-speed treadmill for 1 wk, all horses were exercise trained for 7 wk (22-27). Thereafter, separate trials were undertaken to determine the work intensity eliciting maximal heart rate and stress failure of pulmonary capillaries (39), leading to exercise-induced pulmonary hemorrhage (EIPH). Galloping at 14 m/s on a 3.5% uphill grade elicited maximal heart rate, induced EIPH in all horses (as demonstrated by the presence of fresh blood in the trachea on postexercise airway endoscopic examination; Refs. 16, 22, 36), and could not be sustained for >120 s, despite vigorous humane encouragement. Thus this workload was selected for further experimentation.

Experimental design and protocol. All horses were studied in the placebo [intravenous (IV) physiological saline] and the NaHCO3 treatments, which were carried out in random order, 7 days apart. All experimentation was carried out at an ambient temperature of 20-21°C.

In the NaHCO3 experiments, ~5 min after completion of baseline measurements (rest 1) on quietly standing horses, 5% NaHCO3 solution (Abbott Laboratories, Deerfield, IL) was administered at 250 mg/kg via a previously positioned catheter in the left jugular vein. For individual horses, the volume of 5% NaHCO3 solution varied from 1,955 to 2,492 ml. Thereafter, horses stood quietly on the treadmill for 15 min. Then blood-gas variables and plasma protein concentrations were determined (preexercise data). In the placebo study, after completion of baseline measurements, an equivalent volume (1,955-2,492 ml) of physiological saline was administered IV, and preexercise measurements were made at corresponding intervals in the NaHCO3 treatment. The sequence of placebo and NaHCO3 experiments was randomized, and 7 days were allowed between treatments on every horse.

On completion of preexercise measurements, exercise began on the high-speed treadmill set at a 3.5% uphill grade in the following manner. Beginning with a walk at 2 m/s for 120 s, the belt speed was raised in increments of 1 m/s every 60 s until the speed was 6 m/s. After the horses had trotted at 6 m/s for 60 s, speed was raised to 8 m/s for 60 s and then to 14 m/s. On completion of 120 s of galloping at 14 m/s on a 3.5% uphill grade, the speed was decreased first to 5 m/s (trot) for 60 s and then to 2 m/s. Horses walked at 2 m/s for 300 s before the treadmill was stopped. In this incremental exercise protocol, along with continuous core temperature measurement, simultaneous arterial and mixed venous blood samples were obtained for determining blood-gas variables at 55-60 s of trotting at 6 m/s; at 55-60 s of exercise at 8 m/s; at 30, 60, 90 and 120 s of maximal exertion; and at 120 s of walk at 2 m/s. Also, plasma protein and mixed venous blood lactate concentrations were determined at 60 s of exercise at 8 m/s, at 120 s of maximal exertion, and at 120 s of walk at 2 m/s.

In both treatments, using a flexible fiber-optic endoscope (Pentax Fiberscopes, Orangeburg, NY), nasopharynx, larynx, and trachea (up to the carina) were examined 45-50 min postexercise to detect the occurrence of EIPH (16, 22, 36).

Experimental procedures. On the day of the study, after local anesthesia in the 17th intercostal space, the abdominal aorta was catheterized percutaneously (23-27). Thereafter, using local infiltration of 2% lidocaine HCl, cardiac catheters (8 F) with tip manometer (Millar Instruments, Houston, TX), fluid-filled lumen, and a thermistor (Edward Laboratories, Santa Clara, CA) were advanced into the pulmonary artery via introducers inserted into the left jugular vein. The catheter locations were confirmed by monitoring the characteristic phasic blood pressure waveforms on an oscillograph (E for M, Lanexa, KS). These catheters permitted simultaneous sampling of the aortic and pulmonary arterial (mixed venous) blood, as well as continuous monitoring of the pulmonary arterial blood (core) temperature during the experiments. After catheter placement, horses stood quietly on the treadmill for at least 45-50 min before baseline measurements were initiated.

Because higher osmolality of the 5% NaHCO3 solution [1,190 mosmol/kgH2O vs. that of physiological saline (308 mosmol/kgH2O)] causes water absorption into the vascular compartment, the associated alterations in plasma volume or hydration status were assessed by monitoring changes in the plasma protein concentration (2, 7, 25). Because the quantity of circulating plasma proteins is constant in healthy animals, acute changes in plasma protein concentration are indicative of the changes in the plasma volume or hydration status (2, 7, 25). Plasma protein concentration was determined by refractometry (7, 25), and the %change in plasma volume was calculated as [(PP1/PP2) - 1.0] x 100, where PP1 and PP2 are the initial and the test plasma protein concentrations, respectively (2, 7, 25). Blood-gas variables were determined by using a calibrated blood-gas analyzer and CO-oximeter (ABL520, Radiometer, Copenhagen, Denmark), and all blood-gas tensions and pH data were corrected to the simultaneously measured pulmonary artery blood temperature. Mixed venous blood lactate concentration was also determined (23, 25, 26), and %O2 extraction was calculated as (arterial-to-mixed venous blood O2 content gradient/arterial O2 content) x 100.

Data analysis. The data were subjected to repeated-measures, split-plot design analysis of variance (SAS statistical software version 8.2, SAS Institute, Cary, NC), and the treatment comparisons were made by using the least squares significant difference method (35). Data for the placebo as well as the NaHCO3 experiments were also individually subjected to analysis of variance followed by Newman-Keuls multiple-range test (35) to determine the significant effects of work intensity and duration within each treatment. For all statistical analyses, the level of significance was set at P < 0.05. The data are presented as means ± SE.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Arterial bicarbonate concentration and pH. See Fig. 1. The IV administration of NaHCO3 was well tolerated by the horses. Preexercise arterial pH increased to 7.494 ± 0.004 (vs. 7.401 ± 0.003 pre-NaHCO3 administration; P < 0.0001) as arterial bicarbonate concentration increased to 36.3 ± 0.3 mM. Submaximal exercise in either treatment was not attended by changes in arterial pH from respective preexercise values. However, acidosis developed during maximal exercise in both treatments as blood lactate concentration increased markedly (Fig. 2). Although the extent of the net drop in arterial pH from the beginning to the end of maximal exertion (change in pH = 0.306 ± 0.020 and 0.310 ± 0.018 in the placebo and NaHCO3 experiments, respectively) was not different between treatments, the arterial pH was maintained at a higher value (P < 0.001) in the NaHCO3 experiments. At 120 s of maximal exercise, the arterial pH values in the placebo and NaHCO3 experiments were 7.099 ± 0.028 and 7.177 ± 0.021, respectively (P < 0.001).



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  		Fig. 1. Arterial pH increased markedly following intravenous (IV) administration of NaHCO3 to standing horses. A: whereas arterial pH did not change with submaximal exercise in either treatment, acidosis developed during maximal exertion. B: however, the higher plasma bicarbonate concentration in the NaHCO3-treated horses allowed arterial pH to remain higher than in the placebo study during exercise. Rest #1, baseline measurements made before IV administration of placebo or NaHCO3. Values are means ± SE. *Statistically significant difference from corresponding values in the placebo study, P < 0.001. {alpha}Statistically significant difference from immediately preceding data in the same treatment, P < 0.01. {Phi}Statistically significant difference from data for rest #1, preexercise, and submaximal exercise performed at 6 and 8 m/s in the same study, P < 0.01.

 


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  		Fig. 2. Exercise-induced increment in blood lactate concentration was found to be similar in the placebo and NaHCO3 treatments. Values are means ± SE. {alpha}Statistically significant difference from rest #1 as well as preexercise values in the same treatment, P < 0.0001. {beta}Statistically significant difference from data for 8 m/s in the same treatment, P < 0.0001.

 

Plasma protein and hemoglobin concentrations. See Fig. 3. Following IV NaHCO3 administration to standing horses, plasma protein concentration decreased (P < 0.0001) as 14.6 ± 0.6% expansion of the plasma volume occurred. Concomitantly, hemoglobin concentration also decreased (P < 0.01) in the NaHCO3-treated horses. Incremental exercise in both treatments caused progressive increments in these variables; however, values observed in the NaHCO3 experiments remained less than in the placebo study, indicating that expansion of the plasma volume persisted during exertion. Plasma volume in the NaHCO3 experiments exceeded that in the placebo study by 12.7 ± 0.9% at 60 s of exercise at 8 m/s and by 10.7 ± 1.4% at 120 s of maximal exercise. Arterial hemoglobin concentration approached 22.2 ± 0.3 and 21.1 ± 0.3 g/dl at 120 s of maximal exertion in the placebo and NaHCO3 experiments, respectively (P < 0.01).



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  		Fig. 3. Concentrations of plasma protein (A) and hemoglobin (B) decreased following IV administration of NaHCO3 to standing horses, indicating an expansion of plasma volume. With exercise, plasma protein and hemoglobin concentrations increased in both treatments; however, the values in the NaHCO3 experiments were significantly less than in the placebo study, indicating that the expansion of plasma volume persisted during exertion. Values are means ± SE. *Statistically significant difference from corresponding values in the placebo study (A: P < 0.0001; B: P < 0.01). {Phi}Statistically significant difference from all exercise data in the same treatment, P < 0.0001. {Delta}Statistically significant difference from rest #1 in the same treatment P < 0.0001. {alpha}Statistically significant difference from preexercise values in the same treatment, P < 0.01. {beta}Statistically significant difference from 6 m/s in the same study, P < 0.05. {delta}Statistically significant difference from 8 m/s in the same study, P < 0.0001.

 

Core temperature. See Fig. 4. The incremental exercise protocol caused a similar, progressive rise in core temperature as exercise duration increased in both treatments. At 120 s of maximal exertion, core temperature had increased by 3.4 ± 0.04 and 3.3 ± 0.04°C in the placebo and NaHCO3 experiments, respectively.



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  		Fig. 4. Core temperature of horses increased progressively to similar values with increasing work intensity and duration in both treatments. Values are means ± SE. {Phi}Statistically significant difference from immediately preceding value in the same treatment, P < 0.01.

 

Arterial O2 tension and hemoglobin-O2 saturation. See Fig. 5. Preexercise data for these variables were similar in the placebo and NaHCO3 treatments, and, during exercise performed at 6 and 8 m/s, arterial O2 tension and hemoglobin-O2 saturation were well maintained.



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  		Fig. 5. Changes in arterial O2 tension and hemoglobin-O2 saturation were not observed following IV administration of NaHCO3 to standing horses. A: although arterial O2 tension and hemoglobin-O2 saturation were well maintained during submaximal exercise in both treatments, during maximal exertion a similar drop in arterial O2 tension was observed. B: however, the corresponding desaturation of arterial hemoglobin was significantly greater in the placebo study. Mixed venous blood O2 tension of standing horses decreased following NaHCO3 administration (C), but hemoglobin-O2 saturation was not affected (D). Work intensity-related reductions in mixed venous blood O2 tension and hemoglobin-O2 saturation were observed in both treatments. Values are means ± SE. *Statistically significant difference from corresponding values in the placebo study, P < 0.05. {Phi}Statistically significant difference from all data for rest #1, preexercise, as well as submaximal exercise at 6 and 8 m/s in the same treatment, P < 0.0001. {alpha}Statistically significant difference from immediately preceding data in the same treatment, P < 0.05. {delta}Statistically significant difference from rest #1 and preexercise data in the same treatment, P < 0.0001. {Delta}Statistically significant difference from all data for preexercise as well as submaximal and maximal exercise in the same treatment, P < 0.001.

 

Maximal exercise was attended by a marked reduction of a similar magnitude in arterial O2 tension in both treatments (Fig. 5A). As exercise duration progressed from 30 to 120 s, arterial O2 tension did not change significantly in either treatment. At 120 s of maximal exercise in the placebo and NaHCO3 experiments, the arterial O2 tension was 72.4 ± 2.0 and 69.3 ± 1.8 Torr, respectively (vs. 101.5 ± 0.8 and 99.7 ± 1.1 Torr preexercise, respectively; both P < 0.0001).

Desaturation of arterial hemoglobin was also evident at 30 s of maximal exercise in both treatments, and, as exercise duration progressed to 120 s, the desaturation of arterial hemoglobin intensified (Fig. 5B). However, arterial hemoglobin-O2 saturation was higher (P < 0.05) in the NaHCO3 experiments. At 120 s of maximal exercise in the placebo and the NaHCO3 experiments, arterial hemoglobin-O2 saturation was 84.7 ± 1.7 and 86.8 ± 1.3%, respectively.

Mixed venous blood O2 tension and hemoglobin-O2 saturation. See Fig. 5. Following NaHCO3 administration, preexercise mixed venous blood O2 tension decreased, but hemoglobin-O2 saturation remained unaffected. The incremental exercise protocol caused work intensity-related reductions in these variables in both treatments. From our data, O2 tension required for half-maximal saturation of the blood could not be determined at rest or during maximal exercise. During submaximal exertion, at ~50% O2 saturation of hemoglobin in the mixed venous blood, partial pressure of O2 in individual horses was 2.5-4 Torr less in the NaHCO3 treatment (vs. placebo). However, during maximal exercise, at 9-12.5% O2 saturation of hemoglobin in the mixed venous blood, the partial pressure of O2 in the NaHCO3-treated horses was 1.0-1.5 Torr less than in the placebo treatment.

Arterial CO2 tension. See Fig. 6. Preexercise values of arterial CO2 tension increased (P < 0.05) following NaHCO3 administration. Whereas submaximal exercise was attended by a reduction in arterial CO2 tension, hypercapnia of a similar magnitude developed during maximal exercise in both treatments. At 120 s of maximal exertion in the placebo and the NaHCO3 experiments, arterial CO2 tension had reached 55.4 ± 1.9 and 56.8 ± 1.6 Torr, respectively. During recovery from high-intensity exercise, a dramatic hyperventilation ensued in both treatments, as demonstrated by the large reduction in arterial CO2 tension.



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  		Fig. 6. Although arterial blood CO2 tension of standing horses increased following IV NaHCO3 administration, there were no differences between treatments during exercise. In both treatments, hypercapnia of a similar magnitude was observed during maximal exertion. Values are means ± SE. *Statistically significant difference from corresponding values in the placebo study, P < 0.05. {alpha}Statistically significant difference from immediately preceding data in the same treatment, P < 0.05. {delta}Statistically significant difference from preexercise data in the same treatment, P < 0.05. {theta}Statistically significant difference from values at 30 s of galloping in the same treatment, P < 0.05. {Phi}Statistically significant difference from all data for rest #1, preexercise, as well as submaximal exercise at 6 and 8 m/s in the same treatment, P < 0.0001. {Delta}Statistically significant difference from all data for rest #1, preexercise, as well as submaximal and maximal exercise in the same treatment, P < 0.0001.

 

Arterial and mixed venous blood O2 contents. See Fig. 7. Hemodilution in the NaHCO3 experiments (Fig. 3B) caused the preexercise arterial and mixed venous blood O2 contents (16.0 ± 0.4 and 11.5 ± 0.4 ml O2/dl blood, respectively) to be less than corresponding values in the placebo study (P < 0.01), but the arterial-to-mixed venous blood O2 content gradient remained unaffected.



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  		Fig. 7. A: following IV NaHCO3 administration, the lower hemoglobin concentration (Fig. 3) caused preexercise arterial blood O2 content (CaO2) to decrease. This was accompanied by a reduction in the mixed venous blood O2 content (CO2). During exercise, the increments in CaO2 of the NaHCO3-treated horses were attenuated as well. B: despite the above changes in CaO2 and CO2 in the NaHCO3-treated horses, preexercise CaO2-to-CO2 gradient was unaffected. However, significant differences between treatments were observed during exercise. Values are means ± SE. *Statistically significant difference from corresponding values in the placebo study, P < 0.01. {Phi}Statistically significant difference from all exercise data in the same treatment, P < 0.01. {alpha}Statistically significant difference from immediately preceding data in the same treatment, P < 0.01. {delta}Statistically significant difference from rest #1, preexercise data, and data for exercise at 8 m/s in the same treatment, P < 0.01. {theta}Statistically significant difference from 60 s of galloping in the same treatment, P < 0.01.

 

In both treatments, a significant (P < 0.0001) increment in arterial blood O2 content was observed during exercise as hemoglobin concentration increased. However, because of the attenuated increment in hemoglobin concentration in the NaHCO3-treated horses (Fig. 3B), the increment in arterial O2 content was also attenuated (P < 0.01). At 120 s of maximal exertion, arterial blood O2 content in the placebo and the NaHCO3 treatments was 25.7 ± 0.4 and 24.5 ± 0.3 ml O2/dl of blood, respectively (P < 0.01).

Work intensity-related changes in the mixed venous blood O2 content, arterial-to-mixed venous blood O2 content gradient, and O2 extraction were observed in both treatments. However, the arterial-to-mixed venous blood O2 content gradient of exercising horses in the NaHCO3 experiments remained less than corresponding values in the placebo study (P < 0.01). At 120 s of maximal exercise, the arterial-to-mixed venous blood O2 content gradient in the placebo and NaHCO3 experiments was 23.3 ± 0.4 and 22.2 ± 0.3 ml O2/dl of blood, respectively.

Airway endoscopy. All horses were observed to have experienced EIPH in both treatments.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Our observations in the placebo study regarding arterial hypoxemia, desaturation of hemoglobin, hypercapnia, acidosis, hyperthermia, increased plasma protein and hemoglobin concentrations, as well as increased O2 extraction in horses performing short-term, high-intensity exercise (Figs. 1, 2, 3, 4, 5, 6, 7) mirrored data reported previously (23-27). Our primary objective in this study was to examine whether preexercise NaHCO3 administration exaggerates the exercise-induced arterial hypoxemia as reported by Lloyd et al. (20) and thereby adversely affects the arterial hemoglobin-O2 saturation and O2 content in Thoroughbred horses performing strenuous exercise. In this context, the major findings of the present study were as follows. 1) Preexercise IV NaHCO3 administration did not affect the arterial O2 tension in healthy Thoroughbreds at rest, during submaximal exercise, or during short-term, high-intensity exercise (Fig. 5A), which elicited maximal heart rate and caused stress failure of pulmonary capillaries resulting in EIPH. Thus preexercise induction of metabolic alkalosis (Fig. 1) did not affect the development and/or severity of arterial hypoxemia in maximally exercising Thoroughbreds. Although these findings conflict with those of Lloyd et al. in horses premedicated with NaHCO3, they are in agreement with data in human subjects (28) that preexercise NaHCO3 administration does not affect arterial O2 tension during exertion. 2) In agreement with data in human subjects (28), we also observed an attenuation of the desaturation of arterial hemoglobin during short-term, high-intensity exercise in Thoroughbreds premedicated with NaHCO3 (Fig. 5B). 3) Despite these observations, however, the arterial blood O2 content in the NaHCO3 experiments decreased both preexercise as well as during exercise (Fig. 7). This was a consequence of the hemodilution that ensued following IV NaHCO3 infusion (Fig. 3). 4) An attenuation of the exercise-induced expansion of the arterial-to-mixed venous blood O2 content gradient occurred in the NaHCO3 experiments (Fig. 7).

In agreement with previous work (23-27), we observed in both treatments that arterial hypoxemia was well developed, even at 30 s of maximal exertion, and that further significant changes in arterial O2 tension did not occur as exercise duration progressed to 120 s (Fig. 5). Recently, it was suggested that pulmonary injury (i.e., capillary stress failure)-induced airway inflammatory mediator release plays a role in bringing about the exercise-induced arterial hypoxemia (30, 31). All horses in the present study had experienced EIPH in both treatments, indicating that pulmonary capillary stress failure had occurred (39). According to the pulmonary injury-evoked airway inflammatory mediator release hypothesis (30, 31), an exaggeration of the arterial hypoxemia would be expected to occur with increasing exercise duration as structural changes in the blood-gas barrier (32, 39) intensify over time. Although this hypothesis has considerable appeal, the findings of Wetter et al. (40, 41) in exercising human subjects did not lend credence to it. Similarly, pretreatment of Thoroughbred horses with dexamethasone (to suppress the airway inflammatory response) and with a potent antihistaminic agent (H1-receptor antagonist, tripelennamine HCl, to mitigate the effects of airway inflammatory and mast cell-released histamine on pulmonary capillary permeability) also did not support the pulmonary injury hypothesis for exercise-induced arterial hypoxemia in racehorses (26, 27). Furthermore, blood-gas studies during a repeat bout of strenuous exercise performed soon after the first exercise bout have also discounted the importance of structural changes in the blood-gas barrier (32, 39) in bringing about the exercise-induced arterial hypoxemia in human subjects as well as horses (4, 11, 23, 34). Among the causes of exercise-induced arterial hypoxemia in racehorses are the diffusion limitation to transfer of O2 in the lungs (due to a significantly shortened pulmonary capillary transit time), the so-called relative alveolar hypoventilation [as indicated by the exercise-induced arterial hypercapnia (Fig. 6), despite significantly increased alveolar ventilation], and the ventilation-perfusion inequality (5, 19, 37). The contribution of relative alveolar hypoventilation to exercise-induced arterial hypoxemia would have been similar in our placebo and the NaHCO3 treatments, as indicated by the similarity of arterial CO2 tension during maximal exercise (Fig. 6). Although NaHCO3 administration caused CO2 retention in standing horses, arterial CO2 tension during maximal exercise was not different from values in the placebo study. It is known that, despite synchronization of respiratory and stride frequencies in galloping horses, minute ventilation is not mechanically limited, as significant increments in tidal volume have been demonstrated on increasing treadmill slope at constant speed (3) and with a reduction in inspired O2 concentration (29). This may account for the similarity of arterial CO2 tension in exercising horses in the placebo and the NaHCO3 treatments (Fig. 6).

Although in agreement with previous work (23-27), desaturation of arterial hemoglobin was observed during maximal exertion in both treatments (which intensified as exercise duration progressed to 120 s); an important finding in the present study was the significant attenuation of the desaturation of arterial hemoglobin in the NaHCO3 experiments (Fig. 5B). Because arterial O2 tension had not changed significantly in going from 30 to 120 s of maximal exercise in either treatment, it is likely that the intensification of the desaturation of arterial hemoglobin with increasing exercise duration was caused by the progressive rightward shift of the hemoglobin-O2 dissociation curve as hyperthermia (Fig. 4), acidosis (Fig. 1), and hypercapnia (Fig. 6) intensified over time. Although the extent of exercise-induced hyperthermia, acidosis, and arterial hypercapnia was similar in the two treatments, the fact is that arterial pH of the exercising horses in the NaHCO3 experiments was maintained at a significantly higher value (Fig. 1). The higher arterial pH of NaHCO3-treated horses during galloping at 14 m/s on a 3.5% uphill grade likely contributed to the observed attenuation of the desaturation of arterial hemoglobin by limiting the extent of rightward shift of the hemoglobin-O2 dissociation curve. Despite these findings, the fact is that the arterial blood O2 content of exercising horses in the NaHCO3 treatment was significantly less than that in the placebo study (Fig. 7). This was because of the significant hemodilution that ensued following IV administration of NaHCO3 (Fig. 3). Erythrocyte 2,3-diphosphoglycerate is another factor known to influence the position of the hemoglobin-O2 dissociation curve; however, differences in this variable between the placebo vs. NaHCO3 treatments were not examined in the present study.

In the NaHCO3-treated horses, a significant expansion of the plasma volume was demonstrated by the markedly diminished concentrations of plasma protein and hemoglobin (2, 7, 25), both preexercise as well as during exercise (Fig. 3). Although the hemodilution caused on NaHCO3 administration did not significantly affect the arterial-to-mixed venous blood O2 content gradient in standing horses, a significant (P < 0.01) attenuation of the exercise-induced expansion of the arterial-to-mixed venous blood O2 content gradient was observed (Fig. 7). Whole body O2 consumption is the product of cardiac output and arterial-to-mixed venous blood O2 content gradient (Fick principle). Thus, because NaHCO3 administration does not affect O2 max (8, 20, 21, 28), it follows that the smaller arterial-to-mixed venous blood O2 content gradient of maximally exercising horses in the NaHCO3 experiments (Fig. 7) would have been attended by an augmented cardiac output. Preexercise hypervolemia-induced further significant increase in cardiac output has been demonstrated in maximally exercising horses (13) and human subjects (14, 38). In maximally exercising horses, a 16% augmentation of cardiac output followed preexercise ~20% expansion of the plasma volume (13). This discussion regarding a further augmentation of cardiac output of maximally exercising horses in the NaHCO3 treatment is relevant to the mechanism(s) for exercise-induced arterial hypoxemia (Fig. 5) in that the largest contribution to exercise-induced arterial hypoxemia in racehorses is from the diffusion limitation to transfer of O2 (37). The latter is probably related to the significant shortening of the transit time for blood in the pulmonary capillaries as cardiac output increases dramatically (5, 13, 19, 37). The scenario that maximally exercising horses in our NaHCO3 experiments may have had augmented cardiac output (13), in turn, suggests that there would have been a further truncation of the already shortened pulmonary capillary transit time during high-intensity exercise, which may have adversely affected the arterial O2 tension. Although this was not found to be the case in the present study (Fig. 5), our findings are in agreement with previous studies in human athletes (38, 42) and in racehorses (25), wherein preexercise hypervolemia also failed to significantly affect the exercise-induced arterial hypoxemia. It is plausible that hypervolemia induced following NaHCO3 administration affected the pulmonary capillary blood volume and the distribution of ventilation-perfusion mismatching within the lungs, thereby affecting the pulmonary gas exchange of exercising horses.

Conflicting views have been presented regarding the ergogenic effects of preexercise NaHCO3 administration to racehorses (1, 6, 8-10, 12, 15, 17, 18, 20, 21, 33). In our experiments, neither were the investigators blinded as to the treatments nor was run time to fatigue determined; therefore, an assessment could not be made in this regard. However, based on our perception of the effort and encouragement required for individual horses to complete the 120 s of galloping at 14 m/s on a 3.5% uphill grade, it is opined that the placebo and NaHCO3 treatments were comparable.

In conclusion, our data demonstrated that preexercise IV administration of NaHCO3 to cause metabolic alkalosis in healthy Thoroughbred horses did not affect the development and/or severity of arterial hypoxemia during short-term, high-intensity exercise that elicited maximal heart rate and caused stress failure of pulmonary capillaries, resulting in EIPH. However, a significant attenuation of the desaturation of arterial hemoglobin was observed during maximal exercise in the NaHCO3-treated horses, which had higher arterial pH. Despite these observations, the arterial blood O2 content of exercising horses was found to be less in the NaHCO3 experiments because of the hemodilution, and a significant attenuation of the exercise-induced expansion of the arterial-to-mixed venous blood O2 content gradient was observed.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported in part by grants-in-aid from the US Department of Agriculture-Hatch funds and the Illinois Department of Agriculture. The high-speed treadmill at the University of Illinois College of Veterinary Medicine was procured, in part, with financial support provided by the Illinois Thoroughbred and Standardbred Breeder's Fund.


   ACKNOWLEDGMENTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors are extremely grateful to Sarah Humphrey, Tracy DePuy, William Love, Jason Bundy, Walter C. Crackel, and Beth Saupe for excellent technical assistance in carrying out these experiments.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Manohar, 212 Large Animal Clinic, College of Veterinary Medicine, Univ. of Illinois, 1102 W. Hazelwood Drive, Urbana, IL 61802 (E-mail: mmanohar{at}uiuc.edu).

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
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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