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1Division of Physiology, 5Department of Surgery, University of California, San Diego, La Jolla, California; 2Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical Univeristy, Innsbruck, Austria; Departments of 3Physiology and Biophysics and 4Medicine, University of Washington, Seattle, Washington; and 6The Mountain-Whisper-Light Statistical Consulting, Seattle, Washington
Submitted 16 March 2007 ; accepted in final form 23 August 2007
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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O2max. At steady state (
4 min), metabolic and cardiac output data were collected and fluorescent microspheres were injected over 30 s. Later the fluorescent intensity of each color in each 2-cm3 lung piece was determined and regional perfusion was calculated from the weight-normalized fluorescence. Both hypoxia and exercise shifted PBF away from the ventral cranial lung regions toward the dorsal caudal regions of the lung, but hypoxia caused a greater dorsal caudal shift in PBF at rest than did near-maximal exercise in normoxia. The variance in PBF due to hypoxia, exercise, and vascular structure was 16 ± 4.2, 4.0 ± 4.4, and 59.4 ± 11.4%, respectively, and the interaction between hypoxia and exercise represented 12 ± 6.5%. This observation implies that there is already a maximal shift with in PBF with hypoxia in the dorsal-caudal regions in pigs that cannot be exceeded with the addition of exercise. However, exercise greatly increases the pulmonary arterial pressures and therefore the risk of capillary rupture in high flow regions. fluorescent microspheres; ventilation; perfusion; gas exchange
Like humans, pigs appear to be susceptible to HAPE (18) and bronchoalveolar lavage fluid from resting pigs exposed to 48 h of hypoxia shows increased concentrations of red blood cells and protein suggestive of capillary stress failure and early HAPE (18). Studies in resting prone (33) and supine pigs (15) have demonstrated uneven hypoxic pulmonary vasoconstriction, consistent with the patchy edema formation that is characteristic of HAPE. In addition, there appears to be an influence of regional ventilation-perfusion ratio, and areas of low ventilation perfusion ratio tend to vasoconstrict at a higher inspired oxygen concentration than areas of high ventilation-perfusion ratio, and thus ventilation-perfusion heterogeneity may also predispose to uneven pulmonary vasoconstriction and the development of HAPE.
Pigs have been shown to develop increased ventilation-perfusion heterogeneity with exercise (17) as well as brisk hypoxic pulmonary vasoconstriction (34), thus near maximal hypoxic exercise would be expected to provide a very large physiological stress to the pulmonary vascular system in these animals. In horses, exercise has been shown to cause a redistribution of pulmonary blood flow to the dorsal caudal lung regions (4), the site of pulmonary capillary stress failure in this species. However, the combined effects of hypoxia and exercise on regional pulmonary blood flow have not been studied in any species.
Therefore it was the purpose of this study to determine the relative importance of hypoxia, exercise, and the combination of the two stressors on pulmonary blood flow redistribution. We used fluorescent microsphere markers to quantify the spatial redistribution both at rest and during graded exercise at 30, 60, and 90% of O2max in normoxia and moderate hypoxia (FIO2 = 0.125). We hypothesized that hypoxic exercise would cause a greater pulmonary blood flow redistribution than during normoxic exercise because both hypoxia (33) and exercise (4) tend to shift blood flow toward the dorsal-caudal regions.
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METHODS |
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Exercise Testing
O2max testing.
During the week prior to the experiment, the treadmill O2max of each animal in normoxia and breathing 12.5% O2 (hypoxia) was determined. Briefly, each animal was allowed to warm up at a walking pace for 2 min (2 miles/h, 0% grade) and then the treadmill speed and grade were increased at 2-min intervals until the animal did not respond to vigorous humane stimuli. During testing, the animal was cooled using a 21-in. diameter electric fan and frequent spraying with water. The expired port of the Hans Rudolph valve was connected to a heated mixing chamber where gas was continuously sampled and O2 and CO2 concentrations were measured using a mass spectrometer (Perkin-Elmer 1100, Pomona, CA). Expired gas flow was measured by using a pneumotachograph (Fleisch No. 3) and differential pressure transducer (DP45-14, Validyne, Northridge, CA). During hypoxic exercise testing, an inspired oxygen fraction of 0.125 was ensured by connecting the inspired port of the non-rebreathing valve to a Douglas bag using standard respiratory tubing. This acted as a reservoir for the hypoxic gas and was filled from a gas tank of known concentration. The preliminary O2max testing in normoxia and hypoxia was conducted on different days to allow the animal to recover fully between efforts. The results of these tests were used to select workloads that elicited 30, 60, and 90% of O2max.
Catheter implantation.
The pigs were restricted from food overnight prior to surgery. Anesthesia was induced with ketamine (24 mg/kg im), atropine (0.03 mg/kg im), and xylazine (2.2 mg/kg im), and the animal intubated and mechanically ventilated. Anesthesia was maintained using repeated boluses of propofol at 2–4 mg/kg. The animal was kept warm during the surgery using heating pad and 5% dextrose was given via a peripheral venous line at a rate of 300 ml/h. Under sterile conditions, Silastic catheters were placed in the right carotid artery, and the left internal jugular vein. An 8-Fr. catheter sheath (Arrow Arrowflex, Arrow, Reading, PA) was placed in the right external jugular vein, for the introduction of the Swan Ganz catheter on the day of the study. These catheters were exteriorized on the back of the animal adjacent to the spine. The catheter sites were cleaned and catheters were flushed with 1,000 U/ml heparin daily to maintain patency. Animals were given a minimum of 1 wk to recover from surgery prior to further study.
On the day of the experiment, a no. 5 or 7 Fr. triple-lumen Swan Ganz catheter was inserted into the lumen of the right external jugular cannula, advanced via the external jugular vein and into the pulmonary artery using direct pressure monitoring. This catheter was used for the measurement of cardiac output, using either the direct Fick method (sampling of mixed venous blood) or thermodilution, measurement of pulmonary arterial pressure, and blood temperature.
Experimental design.
The experiments took place in a temperature-controlled ventilated room (21–23°C) and the animal was cooled during the exercise portion of the study using a 21-in. diameter electric fan and frequent spraying with water. Data were collected at rest and during the last 2 min of each of the 5-min exercise levels. Each set of measurements included pulmonary arterial pressure measurements, blood temperature, arterial blood gases, mixed expired gases for metabolic rate measurements, and cardiac output. After these data were collected, fluorescent microspheres were injected for measurement of regional pulmonary blood flow (described below). In normoxia, data were collected at rest and after 5 min of exercise at 30, 60, and 90% of the previously determined O2max. In hypoxia, a normoxic rest condition (including microsphere injection) preceded the hypoxic rest condition and the exercise conditions to determine any changes in the animal's baseline condition between study days. Thus there were a total of nine microsphere trials, four in normoxia (rest, 30, 60, and 90% of O2max) and five in hypoxia (normoxic rest, hypoxic rest, 30, 60, and 90% of O2max). The order of inspired oxygen condition (normoxia or hypoxia) was balanced between animals, and the animals were given at least 24 h to recover between the two study days.
Ventilation and metabolic rate measurements. During the study the animals wore the same custom-designed rubber mask as described above and breathed through a non-rebreathing valve as before. Expired gas was continuously sampled from a heated mixing chamber as before and O2 and CO2 concentrations were measured using a mass spectrometer (Perkin-Elmer 1100, Pomona, CA). Expired gas flow was measured by using a pneumotach (Fleisch no. 3) and differential pressure transducer (DP45-14, Validyne, Northridge, CA), as before.
Hemodynamic measurements. The pressure transducers (Statham P23 ID, Oxnard, CA) were zeroed to the level of the right atrium and transducer height and calibration were checked prior to each measurement. Mean arterial and pulmonary arterial pressures were recorded on a strip chart recorder (Gould, model 200, Valleyview, OH) immediately before each set of blood gas measurements. Cardiac output was calculated from the mixed venous, arterial blood, and oxygen consumption measurements using the Fick equation. However, in some animals, there was difficulty in drawing pulmonary mixed venous blood samples during exercise. In these animals, cardiac output was obtained by thermodilution measurements made in triplicate (Cardiac Output Computer 9520A, American Edwards, Irvine, CA).
Blood gas measurements. Three milliliters arterial and pulmonary mixed venous blood gas samples were obtained in the last 2 min of each workload and stored on ice until analyzed for PO2, PCO2, and pH using an IL Synthesis45 blood gas analyzer (Instrumentation Laboratories, Lexington, MA). All blood gas values were corrected for pulmonary arterial blood temperature using correction factors for PO2 for swine and correction factors for PCO2 and pH as determined by Willford and Hill (35).
Measurement of regional pulmonary perfusion.
Fluorescent microspheres (15 µm) to measure blood flow were administered by intravenous injection into the internal jugular vein, with a different color marking flow during each experimental condition. Approximately one million microspheres per condition were injected for a cumulative dose of 9 million microspheres per animal. The microspheres were administered during the final 2 min of each exercise/FIO2 condition, after collection of the arterial blood gases. Following the final run, the animals were given heparin (5,000 U) and papaverine (30 mg) intravenously before being exsanguinated under deep anesthesia. The lungs were excised, washed with saline, inflated to total lung capacity with 
25 cmH2O inflation pressure and dried with warm air for 3 days. Once completely dry, the lungs were coated with Kwik Foam (DAP, Dayton, OH), then suspended vertically in a plastic-lined squared box and embedded in rapidly setting urethane foam (2 lb. Polyol and Isocyanate, International Sales, Seattle, WA). A rigid form was created and a three-dimensional coordinate system was applied. Lungs were diced into 2 cm3 pieces (number of pieces = 1,431 ± 140, mean ± SD), with spatial coordinates assigned and weights recorded for each piece.
Recovery of fluorescence and calculation of flow.
The fluorescent signal for each color was determined by extracting the fluorescent dyes from each piece with an organic solvent (Cellosolve, Sigma-Aldrich) and measuring the concentration of fluorescence in each sample (11). Spillover from adjacent colors was corrected using a matrix inversion method (31). To compare flow among pieces, some being incomplete tissue cubes, each piece was weight normalized by dividing piece fluorescence by piece weight. Flow per piece was expressed as weight-normalized relative (to the mean) flow, WNR
, under a particular condition.
Pieces were grouped on the response pattern of the residuals of their WNR between two conditions. We compared the relative WNR change in response to hypoxia at rest and exercise and the response to exercise at normoxia and hypoxia. In Fig. 1, lung piece distribution is shown in the prone orientation. Pieces that increase WNR by more than 30%, increase WNR by between 10 and 30%, decrease WNR by between 10 and 30%, and decrease WNR by more than 30% for a particular change in condition are shown as red, yellow, light blue, and dark blue. Pieces with change less than ±10% were considered to have no change and were not included in Fig. 1.
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Data are presented as means ± SD. Repeated measures analysis of variance (Statview 4.1, SAS Institute, Cary, NC) was used to analyze changes in the dependent variables due to the effects of exercise, hypoxia, and the exercise-hypoxia interaction. A paired t-test was used to compare normoxic rest to the prehypoxic normoxic rest condition. Statistical significance was defined as P < 0.05.
The variation in relative flow (WNR) as described in our previous study of exercising horses (4) was partitioned as follows: 1) a component of variation in WNR due to spatial location of the pieces within the lung; 2) a component of variation representing the exercise effect (the difference between rest and exercise at 90% O2max); 3) a component of variation representing the hypoxia effect (the difference between normoxia and hypoxia); and 4) a component of variation representing the interaction between hypoxia and exercise. (This last component of variation also includes temporal variation and measurement error).
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RESULTS |
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O2max in normoxic and hypoxic exercise conditions only, except for the correlation between regional blood flow at different levels of exercise. For the most part, the baseline physiological status of the animals as assessed by resting normoxic data obtained on both the normoxic and hypoxic exercise day (Table 1) did not differ between the two exercise testing days. Specifically there was no statistically significant difference for oxygen consumption, ventilation, PaO2, alveolar-arterial partial pressure difference for oxygen (AaDO2), cardiac output, pulmonary arterial pressure, or mean arterial pressure. However, there was a significant difference in baseline PaCO2 and respiratory exchange ratio, between the two study days. This cannot be an ordering effect since the order of the normoxia and hypoxic trials were balanced between animals, such that three animals had the hypoxic trial first and three animals the normoxic trial first.
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Metabolic rate and hemodynamic data for rest and exercise are given in Table 2. Resting oxygen consumption was 0.32 ± 0.09 l/min during normoxic rest and 0.36 ± 0.08 l/min during hypoxic rest and increased significantly (P < 0.0001) during exercise to 1.32 ± 0.20 l/min in normoxia and 1.02 ± 0.04 l/min during hypoxia. Expired ventilation was 13.6 ± 4.6 l/min at rest and as expected, was increased significantly by exercise (P < 0.0001) and with a borderline increase in hypoxia (P = 0.06).
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O2max, mean arterial pressure was not significantly different from that during resting hypoxia. Cardiac output was 6.0 ± 2.8 l/min during normoxic rest and increased significantly with exercise (P < 0.005) to 13.3 ± 1.5 l/min in normoxia. There was no significant effect of FIO2 on exercising cardiac output (P = 0.22), reflecting good matching of the relative workloads between normoxia and hypoxia. Cardiac output at rest was 7.3 ± 3.8 l/min in hypoxia, and increased significantly (P < 0.005) to 13.7 ± 2.2 l/min during hypoxic exercise. Pulmonary arterial pressures averaged 17.6 ± 12.4 mmHg during normoxic rest and 26.5 ± 17.3 during hypoxic rest and increased significantly with exercise (P < 0.05) and hypoxia plus exercise (P < 0.05) to 38.3 ± 5.0 and 45.5 ± 12.3 mmHg, respectively. Pulmonary Gas Exchange
Arterial blood gas data are given in Table 2. Arterial PO2 averaged 90 ± 1 Torr during normoxic rest and decreased to 73 ± 6 Torr during exercise in normoxia (P < 0.005). Hypoxia significantly reduced PaO2 to 41 ± 1 Torr at rest and 42 ± 1 Torr during heavy exercise (P < 0.0001) but the changes between rest and exercise were not significant in hypoxia. There was a corresponding increase in the AaDO2 from 8 ± 3 Torr at rest to 30 ± 8 Torr during heavy exercise (P < 0.0005) in normoxia and from 10 ± 1 Torr at rest to 20 ± 5 Torr in hypoxia (P < 0.005). Arterial PCO2 did not change across exercise levels in normoxia (43.8 ± 2.5 Torr normoxic rest, 48.0 ± 4.7 normoxic exercise, P = 0.5); however, during hypoxia, PaCO2 was reduced from 39.3 ± 2.0 Torr at rest to 34.6 ± 1.4 Torr during heavy hypoxic exercise (P < 0.005), suggesting increased alveolar ventilation in relationship to metabolic rate in hypoxia but not normoxia.
Spatial Redistribution
The redistribution of pulmonary blood flow was quantified by calculating the relative change in pulmonary blood flow between four paired conditions: normoxic rest, hypoxic rest; normoxic rest, normoxic exercise; hypoxic rest, hypoxic exercise; and normoxic exercise, hypoxic exercise. The spatial distributions of change of piece WNR over these paired conditions are shown for one animal in Fig. 1, A–D. For these data, color coding is used to denote the magnitude of the relative change in WNR between two conditions. The lungs are oriented in the prone position with the observer looking from above. The cranial regions are in the lower left. The dorsal caudal regions are in the upper right. The columns of pieces extend in the caudal-cranial direction.
The changes in flow induced by hypoxia at rest are shown in Fig. 1A. The pieces showing increases in relative flow (red = greater than 30% increase and yellow = 10–30% increase ) are located primarily in the dorsal caudal regions. The pieces showing decreases in relative flow (light blue = 10–30% decrease and dark blue = greater than 30% decrease) are located primarily in the cranial ventral region. Hypoxia resulted in the greatest shift in pulmonary blood flow as demonstrated by large number of red pieces in the dorsal caudal aspect of the lungs. The spatial distributions of change of piece WNR from rest to exercise in normoxia are shown in Fig. 1B, color coded by the magnitude of the change in WNR similar to Fig. 1A. There is a shift in relative blood flow from the ventral-cranial regions toward the dorsal regions, but to a lesser magnitude (fewer pieces in red and dark blue) than is the case with hypoxia (Fig. 1A).
Changes in WNR from normoxic exercise to hypoxic exercise are shown in Fig. 1C. The effects of hypoxia during exercise are smaller in magnitude compared with the changes observed with hypoxia at rest (Fig. 1A). Changes in WNR from hypoxic rest to hypoxic exercise are shown in Fig. 1D. Slightly increasing WNR (yellow, increase 10–30%) pieces occur in the in the dorsal-ventral and lateral regions and a decrease in WNR (light, minus 10–30%, and dark minus 30% or greater, blue) in the caudal regions.
Figure 1 demonstrates that the response of regions to hypoxia and exercise are similar, but different in magnitude. As a simple means of characterizing these changes in regional blood flow, the lungs were divided into quadrants (dorsal-caudal, dorsal-cranial, ventral-caudal, and ventral-cranial). The quadrants were defined by two planes intersecting the lung at the median values of the cranial-caudal and the ventral-dorsal piece coordinate. Thus there were an equal number of points on each side of the each plane. The average responses for all animals of mean regional blood flow within each quadrant are shown in Fig. 2. ANOVA showed the following statistically significant effects of hypoxia or exercise or their interaction. Under hypoxia, there was a significant increase in relative blood flow to the dorsal-caudal region and a significant decrease to the ventral-cranial region. There was also a significant shift away from the ventral-caudal related to hypoxia but it occurred only under rest, with little to no additional effect with exercise. This difference in the effect of hypoxia during rest and exercise in the ventral-caudal region was reflected in a statistically significant hypoxia-exercise interaction. We did not detect any statistically significant exercise effect in any of the regions. We did observe a relatively large increase in blood flow in the dorsal-cranial region with exercise (increase of 0.061), but this was marginally significant (P = 0.06). Comparing the regional changes in blood flow from normoxic rest to normoxic exercise (90% O2max), the dorsal-caudal shift in pulmonary blood flow was reduced by 50% compared with the shift with hypoxia at rest. Comparing hypoxic rest with hypoxic exercise, both the dorsal-caudal quadrant and the ventral-cranial quadrant flows decrease and there is an increase in dorsal-cranial blood flow. Thus the shift in pulmonary blood flow toward the dorsal-caudal regions is near maximal with hypoxia at rest. The addition of exercise, which would normally shift blood flow toward the dorsal-caudal regions, now diverts blood flow more toward the dorsal-cranial regions (Fig. 1D).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Methods Evaluation
The methods used in this study have been evaluated before (12, 22) and in our prior papers on hypoxic pulmonary vasoconstriction (15, 29, 33). Fifteen-micrometer diameter fluorescent microspheres are completely entrapped in the small pulmonary arterioles (23) and adequately reflect the regional pulmonary perfusion (2, 22). The lungs were inflated and dried at total lung capacity. There may be some slight distortion of the pulmonary parenchyma compared with in vivo because of the inflation pressure and absence of the physical constraints of the chest wall and diaphragm in vivo. In the prone position, in vivo lung parenchymal density is more uniform (16).
The microsphere method for measuring regional organ perfusion is an established and well-accepted technique (30) for measuring regional blood flow. It is based on the fundamental principle that labeled microspheres lodge within capillary beds in proportion to local blood flow. The microsphere method has been validated in the lung with the use of both radiolabeled red blood cells (3) and a "molecular microspheres" (22). A basic tenet is that injected microspheres are inert and do not alter local flow or resistance. It is argued that microspheres occlude on a fraction of capillaries and do not, therefore, significantly change local vascular resistance. However, there must be an upper limit to the number of microspheres that can be injected without causing hemodynamic changes. Although there is no literature in large animals to support the assumption that injecting microspheres does not alter vascular resistance, in the rat using a pump-perfused lung with a fully dilated circulation, it was found that pulmonary vascular resistance increases by 0.8% for every 100,000 microspheres injected (13). Extrapolating these data from 0.25-kg rats to 25-kg pigs suggests that more than 10 million microspheres would need to be injected to raise vascular resistance 1%. Thus the cumulative dose of 9 million microspheres used in this study likely has a very small effect and the potential influence of this on the results is mitigated by the balanced order of the study design.
Metabolic and Cardiovascular Data
The normoxic O2max of the animals in the present study of 51 ml·kg–1·min–1 is similar to that reported for untrained farm pigs (21), although less than reported for Yucatan miniswine (17). The exercise intensity in the present study was 90% of O2max for both normoxia and hypoxia and was of sufficient intensity that cardiac output was more than doubled during exercise from baseline values. The resting data obtained in the present study do not reflect true resting values, as these animals were chronically instrumented, awake, standing on the treadmill wearing a mask and anticipating exercise. Although these animals were standing quietly, as in previous studies under similar conditions (17), the values for cardiac output are 30% greater than conscious animals under sling restraint (14).
Pulmonary Gas Exchange
In the present study, pigs developed an increase in the AaDO2 during exercise associated with a reduction in PaO2 from the resting values in normoxia but not hypoxia. Exercising pigs were previously shown to develop an increased AaDO2 that was entirely explained by ventilation-perfusion inequality without evidence of pulmonary diffusion limitation or intrapulmonary shunting as measured by the multiple inert gas elimination technique (17). In contrast to moderately trained humans, where 50% of subjects (26) increase A/ inequality, all of the animals in that prior study had increased ventilation-perfusion inequality with exercise. In the present study the increase in the AaDO2 was less during hypoxic exercise than at the same relative intensity in normoxia, which is consistent with ventilation-perfusion inequality being the major contribution to the gas exchange impairment, as a for a given A/ distribution the AaDO2 is reduced in hypoxia.
At rest in normoxia, the arterial PCO2 was elevated compared with the normal values expected for humans, but similar to values previously reported for Yucatan miniswine (17). However, during the prehypoxic baseline conditions, the PaCO2 was elevated for reasons that are unknown. The order of tests was balanced, such that one-half of the animals received this condition first, and the remainder of the experimental conditions were identical to normoxic rest. During normoxic exercise, the PCO2 was increased from resting levels, reflecting reduced alveolar ventilation relative to metabolic rate. The reason for this is uncertain and may reflect mechanical limitation of ventilation secondarily to locomotor-respiratory coupling, similar to that observed with horses, although it has not been previously reported in exercising miniswine. Locomotor-respiratory coupling would be more likely in normoxia since the additional chemical stimulation induced by hypoxia has been shown to lessen the coupling, albeit at the expense of a greater work of breathing (6). Another possibility is the behavioral effect of wearing a mask on alveolar ventilation; however, this would seem to be unlikely since during both hypoxic rest and exercise PaCO2 was reduced from baseline.
Pulmonary Arterial Pressure
The pig was previously shown to increase pulmonary arterial pressure with exercise (17) and with hypoxia (19, 34); however, to our knowledge, the effects of hypoxic exercise on pulmonary arterial pressure in pigs has not been previously reported. The pig is known to have thick-walled muscular pulmonary arteries and a brisk pulmonary vasoconstrictor response to hypoxia, which may be related to lack of collateral ventilation (17). In the present study, normoxic exercise more than doubled pulmonary arterial pressure, whereas hypoxia at rest increased it by 50%. The combination of hypoxia and exercise increased pulmonary arterial pressure to 260% of its baseline values, thus the effects of hypoxia and exercise on pulmonary arterial pressure appear to be additive.
Pulmonary Blood Flow Heterogeneity in Pigs
The coefficient of variation of pulmonary blood flow (standard deviation/mean flow) is an overall index of perfusion heterogeneity that does not consider the spatial location of specific pieces of lung. The coefficient of variation was 0.31 at rest in normoxia in the present study and is similar to values obtained in the horse (0.39; Ref. 4) and slightly less than values reported for the dog (0.47; Ref. 27) and the sheep (0.51; Ref. 24). Similar to the horse, the coefficient of variation did not change significantly with exercise and no change was observed with hypoxia. The anatomic stability of perfusion can be evaluated from the variance analysis, and 60% of the variance in regional perfusion was explained by structural factors and irrespective of the condition applied, pieces that were high flow remained high flow across the imposed conditions. These values are less than reported for the exercising horse where structure explained almost 70% of the variance.
Mechanisms of Pulmonary Blood Flow Redistribution With Hypoxia and Exercise
The redistribution of blood flow with hypoxia at rest is similar to that described in our previous publication (33) in which we used several graded levels of hypoxia in anesthetized pigs in the prone posture. In this experiment, only one level (FIO2 = 0.125) of hypoxia was used, because in the resting pig the changes in pulmonary vascular resistance are greatest between 11 and 13% inspired oxygen concentration (33).
One possible mechanism for the redistribution of pulmonary blood flow in hypoxia is the rise in pulmonary arterial pressure alone, as predicted by the gravitational zone model. However, the influence of gravity has been shown to have a relatively minor effect on pulmonary perfusion (12). In keeping with this idea, the redistribution of pulmonary blood flow in the present study is less in maximal normoxic exercise than is observed with resting hypoxia, despite an almost 50% greater pulmonary arterial pressure. For technical reasons we did not collect pulmonary arterial wedge pressure; however, assuming that the ratio of pulmonary arterial pressure to cardiac output reflects the directional changes in pulmonary vascular resistance this also corresponded to the greatest change in pulmonary vascular resistance. Resting hypoxia increased the pulmonary arterial pressure/cardiac output ratio by over 50%, whereas in normoxic exercise it was virtually unchanged from normoxic rest (–6%) and during exercise in hypoxia it was elevated only 26% from resting normoxia.
The redistribution of pulmonary blood flow with hypoxia is likely secondary to a spatial heterogeneity in the hypoxic vasoconstriction response among different regions. The dorsal-caudal regions have been shown to have a weaker constrictive response to hypoxia compared with the ventral-cranial regions, and the net result is that pulmonary blood flow decreases in the ventral-cranial regions and shifts toward the dorsal-caudal regions (33). This pattern of response is similar to that in the present study as shown in Fig. 1A. Possible mechanisms for variation in the local hypoxic vasoconstriction may be local differences in release or sensitivity to mediators such as nitric oxide among others. Under normal physiological conditions, nitric oxide is continually released by endothelial cells to regulate organ perfusion pressure and flow (26) and contributes to the maintenance of normal pulmonary vasomotor tone. Cyclooxygenase inhibitors (7) and inhibitors of synthesis or the effect of nitric oxide (5, 20, 32) have been shown to enhance hypoxic pulmonary vasoconstriction, suggesting that the release of endogenous prostaglandins and nitric oxide inhibits hypoxic pulmonary vasoconstriction. Thus heterogeneity in either nitric oxide synthesis or response to nitric oxide in some regions of the pulmonary vasculature could contribute to regional changes in blood flow. In keeping with this idea, the dorsal-caudal pig lung has been shown to have greater calcium-dependent nitric oxide synthase activity than the ventral regions (28).
Relative Interaction Between Hypoxia and Exercise
The redistribution of pulmonary blood flow is similar, but not identical, for both hypoxia and exercise (Fig. 1, A and B). In both cases pulmonary blood flow shifts toward the dorsal-caudal regions. However, the magnitude of shift is greater for hypoxia than it is for exercise, implying a greater difference between the strong and weak responding regions. A similar story comes from the variance analysis. Hypoxia accounts for 16% of the variance and exercise accounts for only 4% of the variance, while the hypoxia and exercise interaction and vascular structure account for 12 and 59%, respectively. This may be because hypoxia invokes nitric oxide, PGI2, and endothelin-1, while exercise may release nitric oxide alone (25). Adding the pulmonary blood flow affects of both hypoxia and exercise creates a different pattern of redistribution than each does individually. When exercise is added to hypoxia, the pulmonary blood flow does not increase further in the dorsal-caudal regions, rather there is a shift more toward the dorsal-cranial regions (see Fig. 1D). This observation implies that there is already a maximal shift with hypoxia in the dorsal-caudal regions that cannot be exceeded with the addition of exercise. However, the additional rise in pulmonary arterial pressure induced by exercise in hypoxia when combined with this redistribution of pulmonary blood flow greatly increases the mechanical forces placed on these dorsal lung regions.
In conclusion, exercise in hypoxia did not greatly alter the redistribution of pulmonary blood flow induced by hypoxia alone. The role of exercise in the development of HAPE may be that the substantially increased pulmonary arterial pressure in the context of sustained hypoxia increases the possibility of capillary rupture and HAPE in the lung regions receiving the greatest perfusion.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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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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  K. J. Burnham, T. J. Arai, D. J. Dubowitz, A. C. Henderson, S. Holverda, R. B. Buxton, G. K. Prisk, and S. R. Hopkins Pulmonary perfusion heterogeneity is increased by sustained, heavy exercise in humans J Appl Physiol, November 1, 2009; 107(5): 1559 - 1568. [Abstract] [Full Text] [PDF]
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