| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of Veterinary Biosciences and Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
In view of
the suggestion that pulmonary injury-induced release of histamine
and/or other chemical mediators from airway inflammatory and mast cells
contribute to the exercise-induced arterial hypoxemia (EIAH) in human
athletes, we examined the effects of pretreatment with a potent
anti-inflammatory agent, dexamethasone, on EIAH and desaturation of
hemoglobin in horses. Seven healthy, sound, exercise-trained
Thoroughbreds were studied in the control (no medications) experiments,
followed in 7 days by intravenous dexamethasone (0.11 mg·kg
1·day1
for 3 consecutive days) studies. Blood-gas measurements were made at rest and during incremental exercise leading to maximal exertion at 14 m/s on a 3.5% uphill grade. Galloping at this workload induced pulmonary hemorrhage in all horses in both treatments, thereby
indicating that stress failure of pulmonary capillaries had occurred.
In both treatments, significant EIAH, desaturation of hemoglobin,
hypercapnia, acidosis, and hyperthermia developed during maximal
exercise, but significant differences between the control and
dexamethasone treatments were not discerned. The failure of
pretreatment with dexamethasone to significantly affect EIAH suggests
that pulmonary injury-evoked airway inflammatory response may not play
a major role in EIAH in racehorses. However, our observations in both
treatments that EIAH developed quickly (being evident at 30 s of
exertion) and that its severity remained unaffected by increasing
exercise duration (to 120 s) suggest that EIAH has a functional
basis, probably related to significant shortening of the transit time
for blood in the pulmonary capillaries as cardiac output increases dramatically.
blood-gas tensions in exercise; adrenoglucocorticoids; airway inflammation; corticosteroids; horses
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
HUMAN SUBJECTS OFTEN EXHIBIT exercise-induced arterial hypoxemia, which is known to limit exercise performance (8, 27). Recently, it was suggested that capillary stress failure (i.e., pulmonary injury)-induced histamine (and possibly other chemical mediators) release from airway inflammatory and mast cells contributes to the exercise-induced arterial hypoxemia in human athletes (1, 25-27). In support of this argument are the observations that plasma histamine concentration increases in exercising human subjects (1, 25-27) and that inhaled nedocromil sodium, a well-known stabilizer of inflammatory and mast cells used in the management of asthma (6), as well as diphenhydramine HCl, an H1-receptor antagonist, significantly attenuated or alleviated the exercise-induced arterial hypoxemia in human subjects (7, 9, 26).
Similar to human athletes, horses are known to exhibit significant exercise-induced arterial hypoxemia (2, 3, 10, 13, 15, 21-23, 34, 36, 37). Also, because of the high transmural [intracapillary minus perivascular (alveolar)] force exerted onto the blood-gas barrier (17-20, 24) relative to its strength, the incidence of capillary stress failure (4, 38) induced exercise-induced pulmonary hemorrhage (EIPH) in racehorses is rather high (>75%; Refs. 14, 33). Furthermore, histological evidence has been presented that autologous blood introduced into the alveoli of horses with EIPH evokes an inflammatory response (35). Also, there have been reports that racehorses experiencing repeated episodes of EIPH have obstructive small-airway disease (16), wherein release of leukotrienes, histamine, and other inflammatory mediators plays a role (28). In view of these reports (16, 28, 35) and the suggestion that pulmonary injury-induced release of histamine (and/or other chemical mediators) from airway inflammatory and mast cells contributes to the exercise-induced arterial hypoxemia in healthy human subjects (1, 25-27), we became interested in evaluating the role of airway inflammation in bringing about arterial hypoxemia in exercising Thoroughbreds. Although the precise chain of events leading to exercise-induced arterial hypoxemia via the latter mechanism (1, 25-27) remains to be elucidated, it was suggested that inflammatory chemical mediators, particularly histamine, being potent capillary permeability promotants, contribute to the reported interstitial pulmonary edema (29) and, in turn, to ventilation-perfusion mismatching within the lungs, resulting in arterial hypoxemia (26, 27).
Glucocorticoids possess potent anti-inflammatory and immunosuppressive actions, and, because of these well-known properties, their therapeutic use in a variety of inflammatory, allergic, and autoimmune diseases in animals and humans is prevalent (31). It is well known that systemically administered synthetic analogs of adrenoglucocorticoids, viz., dexamethasone and triamacinolone, are particularly effective in the treatment of obstructive small-airway disease (heaves) in horses, wherein release of leukotrienes, histamine, and cytokines from airway inflammatory cells has been demonstrated (28). The multiple mechanisms cited for the anti-inflammatory effects of glucocorticoids include the inhibition of phospholipase A2, causing suppression of the production of arachidonic acid and its metabolites; inhibition of histamine release from the basophils and mast cells; as well as suppression of the production and release of cytokines and acute-phase reactants in macrophages, endothelial cells, lymphocytes, and monocytes (31). Thus, in view of the suggestion that pulmonary injury-induced release of chemical mediators from airway inflammatory and mast cells contributes to exercise-induced arterial hypoxemia (1, 7, 9, 25-27) and that introduction of autologous blood into the airways of horses evokes an inflammatory response (35), we hypothesized that the potent anti-inflammatory and immunosuppressive properties of dexamethasone (curtailing the number of inflammatory cells invading the airways as well as diminishing or inhibiting their release of various chemical mediators; Refs. 28, 31) would attenuate or suppress the development of interstitial pulmonary edema, which, through diminished impediment to O2 diffusion and/or an improvement in ventilation-perfusion mismatching, may mitigate arterial hypoxemia in galloping Thoroughbreds. Thus our objective in the present study was to examine the effects of pretreatment with intravenous (IV) dexamethasone, at a dose known to alleviate obstructive small-airway disease (28), on the arterial hypoxemia and desaturation of hemoglobin in horses performing high-intensity exercise capable of eliciting maximal heart rate and inducing EIPH. Dexamethasone is a synthetic analog of the adrenoglucocorticoids, with ~25-fold anti-inflammatory potency of cortisol (31).
| |
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Horses
Experiments were carried out on seven healthy, sound Thoroughbred horses (3 fillies, 4 geldings), 3-6 yr old and weighing 454.1 ± 13.6 kg. They were exercise trained for a period of 7 wk before the blood-gas and hemodynamic studies were undertaken. The horses were housed in an air-conditioned building and were accustomed to being handled by people. They were fed a diet of alfalfa hay and oats, and free access to water was provided. The horses were dewormed periodically and were inoculated with tetanus toxoid and strangles vaccine. Our protocols and procedures were approved by the Institutional Laboratory Animal Care and Use Committees.Exercise Training
After familiarization with walking, trotting, cantering, and galloping on the high-speed treadmill for 1 wk, all horses were exercise trained for a period of 7 wk before the blood-gas and hemodynamic studies were undertaken. Our exercise-training regimen has been described in detail previously (10, 19-23).Work Intensity Eliciting EIPH
Because occurrence of EIPH demonstrates that capillary stress failure-related pulmonary injury has indeed occurred (4, 12, 38), for the present study we intended to use a workload capable of eliciting EIPH consistently. Trials to ascertain work intensity needed to elicit maximal heart rate and EIPH were undertaken on completion of the above-described exercise training. In agreement with our laboratory's previous work (10, 18, 20-23), it was observed that galloping at 14 m/s on a 3.5% uphill grade not only elicited maximal heart rate but also induced EIPH in all horses as demonstrated by the presence of fresh blood in the trachea on postexercise airway endoscopic examination (14, 17, 33). It was also observed that these horses could not sustain galloping at 14 m/s on a 3.5% uphill grade for >120 s despite vigorous humane encouragement. Thus this workload, i.e., 14 m/s on a 3.5% uphill grade, was selected for further experimentation because it represented a strenuous effort eliciting maximal heart rate and EIPH in the experimental horses.Experimental Design and Protocol
All horses were studied in the control as well as the dexamethasone treatments. Because glucocorticoid administration can have prolonged effects on various physiological functions (31), all horses were first studied in the control experiments, followed in 7 days by the IV dexamethasone studies. All experimentation was carried out in an air-conditioned laboratory, where the ambient temperature was maintained at 20-21°C.Control study. In these experiments, horses received no medication(s). On completion of the blood-gas, pH, and hemodynamic measurements (in duplicate) on quietly standing horses when heart rate and aortic and pulmonary vascular pressures had been stable for at least 10-15 min, exercise was performed 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, belt 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 belt speed was decreased to 5 m/s. After the horses had trotted at 5 m/s for 60 s, the belt speed was decreased to 2 m/s and the horses were walked for 5 min before the treadmill was stopped. In this exercise protocol, along with continuous core temperature measurement, simultaneous aortic and pulmonary arterial (mixed venous) blood samples were obtained for determining blood-gas tensions, pH, hemoglobin concentration, hemoglobin O2 saturation, and O2 content at 55 s of trotting at 6 m/s; at 55 s of exercise at 8 m/s; at 30, 60, 90, and 120 s of galloping at 14 m/s on a 3.5% uphill grade; and at 120 s of walk at 2 m/s. Pulmonary arterial blood samples were also obtained preexercise (at rest), at 60 s of exercise at 8 m/s, and at 120 s of walk at 2 m/s for determining lactate concentration in duplicate by using a chemical assay (Sigma Diagnostics, Sigma Chemical, St. Louis, MO).
Dexamethasone study.
For these experiments, our dexamethasone dosage was based on the widely
used therapeutic dose (0.10 mg/kg) for horses afflicted with
obstructive small-airway disease (heaves), wherein release of various
inflammatory mediators, viz., leukotrienes, histamine, and
cytokines, is known to play a role (28). Thus, in
these experiments, horses received IV dexamethasone (0.11 mg · kg1 · day1) for 3 consecutive days. Ninety minutes after the last injection of
dexamethasone, resting data were obtained (in duplicate) on quietly
standing horses when heart rate and aortic and pulmonary vascular
pressures had been stable for 10-15 min. Thereafter, exercise was
performed on the high-speed treadmill set at a 3.5% uphill grade in
exactly the same manner as described above for the control study. Along
with continuous measurement of core temperature, simultaneous arterial
and mixed venous blood samples were obtained for determining blood-gas
tensions, pH, hemoglobin concentration, hemoglobin O2
saturation, O2 content, and lactate concentration at the
same intervals as in the control study (see above).
Experimental Procedures
On the day of the study, after local anesthesia in the 17th intercostal space, the abdominal aorta was percutaneously catheterized as described previously (10, 20-23). Thereafter, after local infiltration of 2% lidocaine HCl, cardiac catheters (8F) equipped with a 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 locations of various catheters were confirmed by monitoring the characteristic phasic blood pressure waveforms on an oscillographic recorder (E for M, Lanexa, KS). Besides blood pressure monitoring, 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 ~45-50 min before blood-gas and pH studies were undertaken.Blood-gas tensions, pH, hemoglobin concentration, hemoglobin-O2 saturation and O2 content were determined by using a carefully calibrated blood-gas analyzer/CO-oximeter (ABL520 system, Radiometer, Copenhagen, Denmark), and all blood-gas tension and pH data were corrected to the simultaneously measured pulmonary artery blood temperature. The calibration of our blood-gas/pH analyzer/CO-oximeter was checked frequently and was verified by using tonometered solutions of known blood-gas tensions, pH, hemoglobin concentration, and O2 saturation. In the present study, O2 extraction (%) was calculated as (arterial-to-mixed venous blood O2 content gradient/arterial blood O2 content) × 100.
For lactate determinations (10, 21), the mixed venous blood samples obtained at various steps of the protocol were immediately deproteinized with chilled perchloric acid (8% wt/vol). After centrifugation, the supernatant fluid was harvested for lactate assays (Sigma Diagnostics, Sigma Chemical), which were carried out in duplicate.
Postexercise Airway Endoscopic Examination
In both treatments, with use of a flexible fiber-optic endoscope (Pentax Fiberscopes, Orangeburg, NY), careful endoscopic examination of the nasopharynx, larynx, and trachea (up to the carina) was undertaken 45-50 min postexercise (14, 17, 33). The presence of fresh blood in the airway(s) was regarded as indicative of the occurrence of EIPH (14, 17, 33).Statistical Analysis of the Data
All data were subjected to repeated-measures, split-plot design analysis of variance procedure (32) by using the SAS statistical software package (SAS version 8.1, SAS Institute, Cary, NC), and the treatment comparisons were made by using the least squares significant difference method (32). Data for the control as well as the dexamethasone treatments were also individually subjected to Newman-Keuls multiple-range test (Ref. 32; SAS version 8.1, SAS Institute) 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 statistical power of comparisons for various variables in the present study exceeded 80%. The data are presented as means ± SE.| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Changes in Core Temperature
Dexamethasone administration did not significantly affect the core temperature of standing or exercising horses. The incremental treadmill exercise protocol used in the present study caused a significant, progressive rise in core temperature as work intensity and exercise duration increased. At 120 s of galloping at 14 m/s on a 3.5% uphill grade, mean core temperature had increased 3.0°C above the preexercise values in both treatments, and statistically significant differences between the control and dexamethasone experiments could not be discerned.Changes in Arterial O2 Tension and Hemoglobin O2 Saturation
Arterial values of O2 tension and hemoglobin O2 saturation in quietly standing horses were unaffected by dexamethasone administration (Fig. 1). Whereas these variables were well maintained during submaximal exercise performed at 6 and 8 m/s in both treatments, a statistically significant (P < 0.0001) reduction in arterial O2 tension and hemoglobin O2 saturation was observed during galloping at 14 m/s on a 3.5% uphill grade. Statistically significant differences between the control and dexamethasone experiments could not be demonstrated, however. At 120 s of galloping at 14 m/s on a 3.5% uphill grade in the control and dexamethasone experiments, the arterial O2 tension was 69.8 ± 3.6 and 70.5 ± 3.2 Torr, respectively.
|
Whereas in going from 30 s to 120 s of galloping at 14 m/s on
a 3.5% uphill grade, arterial O2 tension did not register
a statistically significant change in either treatment, arterial hemoglobin O2 saturation decreased progressively with
increasing exercise duration as exercise-induced hyperthermia,
hypercapnia (Fig. 2), and metabolic
acidosis (Fig. 3) intensified, causing a
rightward shift of the hemoglobin-O2 dissociation curve. At 120 s of galloping at 14 m/s on a 3.5% uphill grade in the
control and dexamethasone experiments, the arterial hemoglobin
O2 saturation was 82 ± 4 and 83 ± 4%,
respectively, and statistically significant differences between
treatments were not discerned.
|
|
Changes in Mixed Venous O2 Tension and Hemoglobin O2 Saturation
Preexercise values of these variables were similar in the control and dexamethasone experiments (Fig. 1). During exercise, work intensity-related significant reductions in these variables were observed in both treatments, but statistically significant differences between treatments were not found.Changes in Arterial and Mixed Venous Blood CO2 Tension
Dexamethasone administration did not cause statistically significant changes in arterial CO2 tension of standing horses (Fig. 2). In both treatments, whereas submaximal exercise was attended by a significant reduction in arterial CO2 tension, significant hypercapnia developed during galloping at 14 m/s on a 3.5% uphill grade. However, statistically significant differences between the control and dexamethasone treatments could not be demonstrated.As expected, in both treatments mixed venous blood CO2 tension increased progressively with incremental exercise protocol used in the present study. At 60 and 120 s of galloping at 14 m/s on 3.5% uphill grade in the control study, the mixed venous blood CO2 tension approached 110 ± 7 and 136 ± 9 Torr, respectively. Corresponding values in the dexamethasone experiments were 106 ± 7 and 130 ± 10 Torr, respectively, and statistically significant differences (P < 0.6182) between the control and dexamethasone treatments were not discerned. In both treatments, the mixed venous-to-arterial CO2 tension gradient also increased progressively with increasing work intensity. At 60 and 120 s of galloping at 14 m/s on 3.5% uphill grade in the control study, the mixed venous-to-arterial blood CO2 tension gradient was 57 ± 6 and 79 ± 8 Torr, respectively. Corresponding values in the dexamethasone experiments were 55 ± 5 and 77 ± 8 Torr, respectively, and statistically significant differences (P < 0.8191) between the control and dexamethasone treatments were not found.
Changes in Arterial pH and Mixed Venous Blood Lactate Concentration
Preexercise values of these variables were similar in the control and dexamethasone experiments (Fig. 3). In both treatments, although arterial pH was well maintained during submaximal exercise, a significant, progressive acidosis developed during galloping at 14 m/s on a 3.5% uphill grade as exercise duration progressed to 120 s. Statistically significant differences between control and dexamethasone treatments regarding arterial pH (P < 0.3198) and blood lactate concentration (P < 0.2613) could not be discerned, however.Changes in Arterial-to-Mixed Venous Blood O2 Content Gradient and O2 Extraction
In standing horses, hemoglobin concentration, arterial and mixed venous blood O2 contents, arteriovenous O2 content gradient, and O2 extraction were unaffected by dexamethasone administration (Fig. 4).
|
Because of splenic release of erythrocyte reservoir, hemoglobin concentration of exercising horses was observed to increase significantly (P < 0.0001) in both treatments; at 120 s of galloping at 14 m/s on a 3.5% uphill grade, arterial hemoglobin concentration had approached 22.0 ± 0.4 and 21.6 ± 0.4 g/dl in the control and the dexamethasone treatments respectively, and statistically significant differences were not discerned. Concomitantly, a significant (P < 0.0001) increment of a similar magnitude in arterial blood O2 content was also observed during exercise, whereas work intensity-related similar changes occurred in the mixed venous blood O2 content in both treatments. Consequently, arterial-to-mixed venous blood O2 content gradient of exercising horses increased significantly (P < 0.0001) in both treatments. At 120 s of galloping at 14 m/s on a 3.5% uphill grade in the control and the dexamethasone experiments, arterial-to-mixed venous blood O2 content gradient was 22.4 ± 1.2 and 21.7 ± 0.9 ml O2/dl blood, respectively, as O2 extraction approached 90.7 ± 0.8 and 91.0 ± 0.9%, respectively. Statistically significant differences between the control and dexamethasone treatments were not found.
Airway Endoscopic Observations
In the control as well as dexamethasone experiments, all horses were observed to have experienced EIPH as demonstrated by the presence of fresh blood in the trachea (14, 17, 33).| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Our primary objective in the present study was to examine whether pretreatment with an anti-inflammatory agent (dexamethasone) would affect the development and/or severity of arterial hypoxemia in horses performing strenuous exercise capable of inducing stress failure of pulmonary capillaries. In this context, our data revealed that IV dexamethasone [administered at a dose known to alleviate obstructive small-airway disease (heaves) in horses; Ref. 28] did not significantly affect the development of arterial hypoxemia and desaturation of hemoglobin or their severity (Fig. 1) during short-term high-intensity exercise that caused pulmonary injury as evidenced by the occurrence of EIPH. These findings suggest that pulmonary injury-evoked airway inflammatory response is unlikely to play a major role in bringing about arterial hypoxemia in galloping Thoroughbreds. Although the reasons for divergent findings of the present study vis-a-vis reports in human subjects after nedocromil and diphenhydramine inhalation (7, 9, 26) are difficult to discern, species differences cannot be ruled out.
In view of the negative findings of the present study vis-a-vis human experiments with nedocromil and diphenhydramine (7, 9, 26), it is important to note that a discrete causal relationship between pulmonary injury and airway inflammation-induced release of histamine (and/or other chemical mediators) and exercise-induced arterial hypoxemia has not been established. In fact, Wetter et al. (39) reported that, although plasma histamine increased in exercising women, it was inversely correlated with severity of arterial hypoxemia at end exercise. Furthermore, it was recently demonstrated that preexercise IV administration of an antihistaminic agent, tripelennamine HCl (a known H1-receptor antagonist), failed to affect the arterial hypoxemia and desaturation of hemoglobin in Thoroughbreds performing high-intensity exercise that induced EIPH (23). Thus it was concluded that pulmonary injury and airway inflammation-induced histamine release may not play a major role in bringing about arterial hypoxemia in exercising horses (23).
The commonly mentioned possible causes of exercise-induced arterial hypoxemia in horses include the so-called "relative" alveolar hypoventilation (Fig. 2), ventilation-perfusion inhomogeneity, and the diffusion limitation related to the significantly shortened transit time for blood in the pulmonary capillaries as cardiac output increases dramatically (2, 3, 10, 13, 15, 21-23, 36, 37). Whereas the similarity of arterial CO2 tension between the control and dexamethasone studies (Fig. 2) indicated similarity of alveolar ventilation in exercising horses, for unexplained reasons Prefaut et al. (26) reported a significant rise in arterial CO2 tension of athletes performing maximal exertion after nedocromil inhalation. Alveolar-to-arterial O2 tension gradient was not determined in the present study; however, the following observations suggest that the respiratory exchange ratio may not have been affected by dexamethasone administration. 1) Throughout the experimental protocol, arterial-to-mixed venous blood O2 content gradient (Fig. 4) and O2 extraction in the dexamethasone treatment were not different from the control study, indicating similarity of the aerobic metabolism in the two treatments. 2) Also, because acidosis (Fig. 3A), mixed venous blood CO2 tension as well as mixed venous-to-arterial blood CO2 tension gradient (cf. RESULTS), and lactate production (Fig. 3B) were not significantly different between the control and dexamethasone treatments, it is suggested that anaerobic metabolism of exercising horses was unaffected as well. Thus it is unlikely that O2 uptake, CO2 production, and respiratory exchange ratio were significantly affected by dexamethasone administration. This coupled with the finding that dexamethasone administration did not significantly affect arterial CO2 and O2 tensions (Figs. 1 and 2) suggests that the alveolar-to-arterial O2 tension gradient may not have changed significantly between the control and dexamethasone treatments. However, because ventilation-perfusion inhomogeneity probably does not play a major role in bringing about the exercise-induced arterial hypoxemia in racehorses, the possibility remains that dexamethasone administration may have affected ventilation-perfusion inequality without significantly affecting the efficiency of pulmonary gas exchange.
In our experiments, arterial hypoxemia was already well developed by 30 s of galloping at 14 m/s on a 3.5% uphill grade, and further significant changes in the arterial O2 tension did not occur as exercise duration progressed to 120 s (Fig. 1). According to the hypothesis that capillary stress failure (4, 12, 38)-related pulmonary injury-evoked airway inflammatory and mast cell histamine release (1, 25-27) leads to interstitial pulmonary edema (29), an accentuation of the arterial hypoxemia would be expected with increasing exercise duration as interstitial pulmonary edema intensifies over time. The fact that this was not the case in our control and/or dexamethasone experiments (Fig. 1), or in previous studies (10, 21-23), argues against a significant role for structural changes in the blood-gas barrier (4, 12, 29, 38) in bringing about the exercise-induced arterial hypoxemia. Further support for this argument is provided by the observation that, during a repeat bout of strenuous exercise performed 6 min after the first exercise bout that caused stress failure of pulmonary capillaries, an accentuation of the arterial hypoxemia could not be demonstrated (21). Similar observations were also reported in human subjects (5, 11, 30), and it was concluded that capillary stress failure-related structural changes in the blood-gas barrier are probably not responsible for the exercise-induced arterial hypoxemia (5, 11, 21, 30). The findings that arterial hypoxemia developed rather quickly, being evident at 30 s of galloping at 14 m/s on a 3.5% uphill grade, and that its severity was not significantly affected by increasing exercise duration in either treatment (Fig. 1) are consistent with the thesis that exercise-induced arterial hypoxemia in racehorses more likely has a functional basis, probably related to significant shortening of the transit time for blood in the pulmonary capillaries as cardiac output increases dramatically (21-23).
A pertinent issue to the present study is whether the occurrence of EIPH evokes airway inflammatory response in horses. Although bronchoalveolar lavage was not performed in our experiments, it should be noted that Tyler et al. (35) demonstrated that introduction of autologous blood into the alveoli of horses (e.g., with EIPH) evoked airway inflammatory response. In the present study, all horses were first studied in the control experiments wherein they experienced EIPH. Thus, based on the findings of Tyler et al., it is presumed that airway inflammatory response may have developed before dexamethasone administration was begun.
In conclusion, the results of the present study demonstrated that pretreatment with IV dexamethasone failed to significantly affect the development and severity of arterial hypoxemia and desaturation of hemoglobin in Thoroughbreds performing strenuous exercise that caused pulmonary injury as evidenced by the occurrence of EIPH. The failure of pretreatment with a potent anti-inflammatory agent to significantly modify exercise-induced arterial hypoxemia suggests that pulmonary injury-evoked airway inflammatory response is unlikely to play a major role in bringing about arterial hypoxemia in galloping Thoroughbred horses.
| |
ACKNOWLEDGEMENTS |
|---|
The authors gratefully acknowledge the excellent technical assistance provided by Audra Kazlauskas, Ragenia Saar, Walter C. Crackel, Tracy Bailey, and Beth Saupe.
| |
FOOTNOTES |
|---|
This work was supported in part by grants-in-aid from the Houston Equine Research Organization, the US Department of Agriculture-Hatch Funds, the Illinois Department of Agriculture Equine Research Fund, and the Illinois Thoroughbred Horsemen's Association. 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.
Address for reprint requests and other correspondence: M. Manohar, College of Veterinary Medicine, Univ. of Illinois, 212 Large Animal Clinic, 1102 West Hazelwood Dr., 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.
First published March 15, 2002;10.1152/japplphysiol.01186.2001
Received 30 November 2001; accepted in final form 11 March 2002.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Anselme, F,
Caillaud C,
Couret I,
Rossi M,
and
Prefaut C.
Histamine and exercise-induced hypoxemia in highly trained athletes.
J Appl Physiol
76:
127-132,
1994
2.
Bayly, WM,
Grant BD,
and
Breeze RG.
The effects of maximal exercise on acid-base balance and arterial blood-gas tension in thoroughbred horses.
In: Equine Exercise Physiology, edited by Snow DH,
Persson SGB,
and Rose RJ.. Cambridge, UK: Granta Editions, 1983, p. 400-407.
3.
Bayly, WM,
Hodgson DR,
Schultz DA,
Dempsey JA,
and
Gollnick PD.
Exercise-induced hypercapnia in the horse.
J Appl Physiol
67:
1858-1866,
1989.
4.
Birks, EK,
Mathieu-Costello O,
Zhenxing F,
Tyler WS,
and
West JB.
Very high pressures are required to cause stress failure of pulmonary capillaries in Thoroughbred racehorses.
J Appl Physiol
82:
1584-1592,
1997
5.
Caillaud, CF,
Anselme FM,
and
Prefaut CG.
Effects of two successive maximal exercise tests on pulmonary gas exchange.
Eur J Appl Physiol
74:
141-147,
1996.
6.
Corin, RE.
Nedocromil sodium: a review of the evidence for a dual mechanism of action.
Clin Exp Allergy
30:
461-468,
2000[Medline].
7.
Coyle, MA,
and
Stager JM.
Exercise-induced hypoxemia is ameliorated by nedocromil sodium and diphenhydramine HCl (Abstract).
Med Sci Sports Exerc
33:
S58,
2001.
8.
Dempsey, JA,
and
Wagner PD.
Exercise-induced arterial hypoxemia.
J Appl Physiol
87:
1997-2006,
1999
9.
Ferguson, CS,
Murphy JD,
Brown KR,
and
Harms CR.
Effect of nedocromil sodium on pulmonary gas exchange and 
O2 max (Abstract).
Med Sci Sports Exerc
33:
S58,
2001.
10.
Goetz, TE,
Manohar M,
Hassan AS,
and
Baker GJ.
Nasal strips do not affect pulmonary gas-exchange, anaerobic metabolism, or EIPH in exercising Thoroughbreds.
J Appl Physiol
90:
2378-2385,
2001
11.
Hanel, B,
Clifford P,
and
Secher N.
Restricted postexercise pulmonary diffusion capacity does not impair maximal transport of O2.
J Appl Physiol
77:
2408-2412,
1994
12.
Hopkins, SR,
Schoene RB,
Martin TR,
Henderson WR,
Spragg RG,
and
West JB.
Intense exercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes.
Am J Respir Crit Care Med
155:
1090-1094,
1997[Abstract].
13.
Jones, JH.
Circulatory function during exercise
integration of convection and diffusion.
In: Comparative Vertebrate Exercise Physiology: Unifying Physiological Principles, edited by Cornelius CE,
Marshak RR,
and Melby EC.. San Diego, CA: Academic, 1994, p. 217-251.
14.
LaPointe, JM,
Vrins A,
and
McCarvill E.
A survey of exercise-induced pulmonary hemorrhage in Quebec Standardbred racehorses.
Equine Vet J
26:
482-485,
1994[ISI][Medline].
15.
Lekeux, P,
and
Art T.
The respiratory system: anatomy, physiology, and adaptations to exercise and training.
In: The Athletic HorsePrinciples and Practice of Equine Sports Medicine, , edited by Hodgson DR,
and Rose RJ.. Philadelphia, PA: Saunders, 1994, p. 79-121.
16.
MacNamara, B,
Bauer S,
and
Iafe J.
Endoscopic evaluation of exercise-induced pulmonary hemorrhage and chronic obstructive pulmonary disease in association with poor performance in racing Standardbreds.
J Am Vet Med Assoc
196:
443-454,
1990[Medline].
17.
Manohar, M,
and
Goetz TE.
Pulmonary vascular pressures of exercising Thoroughbred horses with and without endoscopic evidence of EIPH.
J Appl Physiol
81:
1589-1593,
1996
18.
Manohar, M,
and
Goetz TE.
L-NAME does not affect exercise-induced pulmonary hypertension in Thoroughbred horses.
J Appl Physiol
84:
1902-1908,
1998
19.
Manohar, M,
and
Goetz TE.
Pulmonary vascular pressures of strenuously exercising Thoroughbreds during intravenous infusion of nitroglycerin.
Am J Vet Res
60:
1436-1440,
1999[Medline].
20.
Manohar, M,
and
Goetz TE.
Pulmonary vascular resistance of horses decreases with moderate exercise and remains constant as workload is increased to maximal exercise.
Equine Vet J Suppl
30:
117-121,
1999[Medline].
21.
Manohar, M,
Goetz TE,
and
Hassan AS.
Effect of prior high-intensity exercise on exercise-induced arterial hypoxemia in Thoroughbred horses.
J Appl Physiol
90:
2371-2377,
2001
22.
Manohar, M,
Goetz TE,
and
Hassan AS.
Nitric oxide synthase inhibition does not affect the exercise-induced arterial hypoxemia in Thoroughbred horses.
J Appl Physiol
91:
1105-1112,
2001
23.
Manohar, M,
Goetz TE,
Humphrey S,
and
DePuy T.
H1-receptor antagonist, tripelennamine HCl, does not affect arterial hypoxemia in exercising Thoroughbreds.
J Appl Physiol
92:
1515-1523,
2002
24.
Manohar, M,
Hutchens E,
and
Coney E.
Pulmonary haemodynamics in the exercising horse and their relationship to exercise-induced pulmonary haemorrhage.
Br Vet J
149:
419-428,
1993[ISI][Medline].
25.
Mucci, P,
Durand F,
Lebel B,
Bousquet J,
and
Prefaut C.
Basophils and exercise-induced hypoxemia in extreme athletes.
J Appl Physiol
90:
989-996,
2001
26.
Prefaut, C,
Anselme PF,
and
Caillaud C.
Inhibition of histamine release by nedocromil sodium reduces exercise-induced hypoxemia in master athletes.
Med Sci Sports Exerc
29:
10-16,
1997[ISI][Medline].
27.
Prefaut, C,
Durand F,
Mucci P,
and
Caillaud C.
Exercise-induced arterial hypoxemia in athletes.
Sports Med
30:
47-61,
2000[ISI][Medline].
28.
Robinson, NE.
Pathogenesis and management of airway disease.
Proc Am Assoc Equine Pract
43:
106-115,
1997.
29.
Schaffartzik, W,
Arcos J,
Tsukimoto AK,
Mathieu-Costello O,
and
Wagner PD.
Pulmonary interstitial edema in the pig after heavy exercise.
J Appl Physiol
75:
2535-2540,
1993
30.
St. Croix, CM,
Harms CA,
McClaran SR,
Nickele GA,
Pegelow DF,
Nelson WB,
and
Dempsey JA.
Effects of prior exercise on exercise-induced arterial hypoxemia in young women.
J Appl Physiol
85:
1556-1563,
1998
31.
Schimmer, BP,
and
Parker KL.
Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones.
In: Goodman and Gilman's The Pharmacological Basis of Therapeutics (10th ed.), edited by Hardman JG,
and Limbird LE.. New York: McGraw-Hill, 2001, chapt. 60, p. 1649-1677.
32.
Steel, RGD,
and
Torrie JH.
Principles and Procedures in Statistics (2nd ed.). New York: McGraw-Hill, 1960, p. 138-206.
33.
Sweeney, CR.
Exercise-induced pulmonary hemorrhage.
Vet Clin North Am Equine Pract
7:
93-104,
1991[ISI][Medline].
34.
Thornton, JR,
Essen-Gustavsson B,
and
Lindholm A.
Effects of training and detraining on oxygen uptake, cardiac output, blood-gas tensions, pH and lactate concentrations during and after exercise in the horse.
In: Equine Exercise Physiology, edited by Snow DH,
Persson SGB,
and Rose RJ.. Cambridge, UK: Granta Editions, 1983, p. 470-486.
35.
Tyler, WS,
Pascoe JR,
and
Aguilera-Tejero E.
Morphological effects of autologous blood or saline in airspaces of equine lungs.
In: Proceedings of the International EIPH Conference. Guelph, ON, Canada: Equine Research Centre, 1993, p. 16.
36.
Wagner, PD,
Erickson BK,
Seaman J,
Kubo A,
Hiraga M,
Kai M,
and
Yamaya Y.
Effects of altered FIO2 on maximal O2 in the horse.
Respir Physiol
105:
123-134,
1996[ISI][Medline].
37.
Wagner, PD,
Gillespie JR,
Landgren GL,
Fedde MR,
Jones BW,
DeBowes RM,
Pieschl RL,
and
Erickson HH.
Mechanism of exercise-induced hypoxemia in horses.
J Appl Physiol
66:
1227-1233,
1989
38.
West, JB,
Mathieu-Costello O,
Jones JH,
Birks EK,
Logeman RB,
Pascoe JR,
and
Tyler WS.
Stress failure of pulmonary capillaries in racehorses with exercise-induced pulmonary hemorrhage.
J Appl Physiol
75:
1097-1109,
1993
39.
Wetter, TJ,
St. Croix C,
Pegelow DF,
Sonetti DA,
and
Dempsey JA.
Effects of exhaustive endurance exercise on pulmonary gas exchange and airway function in women.
J Appl Physiol
91:
847-858,
2001
This article has been cited by other articles:
|
|
 |
|
  M. Manohar and T. E. Goetz Intrapulmonary arteriovenous shunts of >15 {micro}m in diameter probably do not contribute to arterial hypoxemia in maximally exercising Thoroughbred horses J Appl Physiol, July 1, 2005; 99(1): 224 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Manohar, T. E. Goetz, and A. S. Hassan NaHCO3 does not affect arterial O2 tension but attenuates desaturation of hemoglobin in maximally exercising Thoroughbreds J Appl Physiol, April 1, 2004; 96(4): 1349 - 1356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Manohar, T. E. Goetz, and A. S. Hassan Preexercise hypervolemia does not affect arterial hypoxemia in Thoroughbreds performing short-term high-intensity exercise J Appl Physiol, June 1, 2003; 94(6): 2135 - 2144. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
Statistically
significant difference from data for rest in the same treatment,
P < 0.0001. 
Statistically
significant difference from data for rest, submaximal exercise
performed at 6 and 8 m/s, as well as recovery (120 s at 2 m/s) in the
same study, P < 0.0001. 
Statistically significant difference from data for
rest and submaximal exercise performed at 6 and 8 m/s in the same
treatment, P < 0.0001. 
Statistically significant difference from data
obtained at 30 s of galloping at 14 m/s on a 3.5% uphill grade in
the same study, P < 0.05. 
Statistically significant difference from data
obtained at 60 s of galloping at 14 m/s on a 3.5% uphill grade in
the same treatment, P < 0.05.
Statistically significant difference from submaximal
exercise performed at 8 m/s in the same study, P < 0.0001. 
