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00005768-200411000-0000900005768_2004_36_1884_cooper_temporal_11article< 82_0_12_3 >Medicine & Science in Sports & Exercise©2004The American College of Sports MedicineVolume 36(11)November 2004pp 1884-1887Temporal Changes in tPA and PAI-1 after Maximal Exercise[Basic Sciences: Original Investigations]COOPER, JAMIE A.; NAGELKIRK, PAUL R.; COUGHLIN, ADAM M.; PIVARNIK, JAMES M.; WOMACK, CHRISTOPHER J.Human Energy Research Laboratory, Department of Kinesiology, Michigan State University, East Lansing, MIAddress for correspondence: Christopher J Womack, Ph.D., FACSM, 3 IM Sports Circle, East Lansing, MI 48824; E-mail: cwomack@msu.edu.Submitted for publication January 2004.Accepted for publication July 2004.ABSTRACTPurpose: Although fibrinolysis increases with acute exercise, it decreases rapidly during the postexercise period. Therefore, the time point at which blood samples are collected postexercise could affect reported tissue plasminogen activator (t-PA) and/or plasminogen activator inhibitor-1 (PAI-1) levels. The purpose of this study was to determine the time course of t-PA and PAI-1 changes after acute maximal exercise.Methods: Eight healthy males performed a graded maximal exercise test on a treadmill. Venous blood samples were collected using an indwelling catheter before exercise and at 1, 2, 4, 6, 8, and 10 min postexercise. Mean differences in t-PA activity, t-PA antigen, and PAI-1 activity at each time point were assessed using a repeated measures ANOVA. Post hoc means comparisons were performed by contrasting the 1-min postexercise value against all other time points.Results: Both t-PA activity and t-PA antigen significantly increased from pre- to postexercise (P < 0.05). t-PA activity did not change from 1 to 2 min postexercise but decreased significantly at 4 min postexercise. Likewise, t-PA antigen remained elevated from 1 to 2 min postexercise but decreased at 4 min postexercise. PAI-1 decreased from pre- to postexercise but did not change during the 10-min postexercise period.Conclusion: To accurately evaluate the t-PA response to acute exercise, blood samples should be collected within 2 min after the cessation of exercise.Fibrinolysis, defined as the capacity to lyse clots, is associated with risk of cardiovascular disease as well as cardiovascular events, such as stroke and myocardial infarction (6,8,12,14,19). During acute exercise, fibrinolysis increases (15,21,24,28,29) due to an increase in tissue plasminogen activator (t-PA) and a decrease in plasminogen activator inhibitor-1 (PAI-1). There has been a growing body of research evaluating acute fibrinolytic response to exercise (5,10,13,15,20,22,26–29); however, there is little standardization regarding the manner of blood collection in these studies.Specifically, there are no current standardized procedures with respect to the timing of postexercise blood collection. Some previous studies evaluating the acute fibrinolytic response to exercise indicate specific time points for blood sampling, such as 1 min (26) or within 2 min (12) postexercise. However, most studies simply report that blood was drawn “immediately” postexercise (9,10,13), leaving it unclear as to exactly when samples were obtained.Timing of postexercise blood sampling is a potentially important methodological issue, as the half-life of t-PA is approximately 3 min (17), and decreases in global fibrinolytic activity have been observed 5 min after exercise (5). Therefore, the time point at which blood samples are collected postexercise could affect reported plasma t-PA and/or PAI-1 levels. However, it is not known how long after exercise cessation that t-PA and PAI-1 begin to change. The purpose of this study was to determine the time course of t-PA and PAI-1 changes after acute maximal exercise, so that an appropriate, standardized time period for postexercise samples could be followed in future studies evaluating the fibrinolytic response to acute exercise. It was hypothesized that t-PA would decrease and PAI-1 would increase in less than 10 min of passive recovery.METHODSApproach to the problem and experimental design.This study used a repeated measures design with time of sampling as the independent variable and tPA activity, tPA antigen, and PAI-1 activity as the dependent variables. Post hoc tests were done using contrasts with the 1-min postexercise value, which was determined a priori to be the criterion postexercise value.Subjects.Eight healthy males with the following characteristics (data listed as mean ± SD): age = 21.5 ± 1.5 yr, height = 179.3 ± 7.75 cm, weight = 77.04 ± 12.11 kg were recruited from Michigan State University. Before beginning the study, written informed consent was obtained from all subjects. The study was approved by the Michigan State University Committee on Research Involving Human Subjects. Written informed consent was obtained from each subject before participation. Subjects had no known cardiovascular or metabolic disease, did not use tobacco, were not taking any medications, and were free from infection, fever, or illness for at least 2 wk before testing.Treadmill testing.After a 12-h fast, subjects reported to the lab between 0700 and 1000 to control for diurnal variation in fibrinolysis (1). Each subject performed a graded exercise test using a treadmill ramped protocol. Treadmill velocity began at 2.5 mph and increased at a rate of 0.5 mph per minute until reaching 6.0 mph, after which speed remained constant and grade increased at a rate of 3% per minute until volitional exhaustion. Heart rate (HR) was recorded using a Polar HR telemetry system (Gays Mills, WI), and V̇O2 was measured using a SensorMedics 2900 metabolic measurement cart (Yorba Linda, CA).Blood sampling.All subjects assumed a semirecumbent position for 30 min before obtaining the baseline blood sample to control for any postural effects on fibrinolysis (27). Blood samples were collected using an indwelling catheter immediately before exercise and at 1, 2, 4, 6, 8, and 10 min postexercise. The catheter line was kept patent by infusing saline solution. For each sample, approximately 5 mL of venous blood was discarded before drawing five additional mL into a chilled acidified citrate tube (Biopool, International, Ventura, CA). Roughly, 1 mL of whole blood from the samples was used to determine hematocrit (microhematocrit method) and blood lactate concentration [La−] (YSI 2300 Stat Plus blood chemistry analyzer, Yellow Springs Instruments, Yellow Springs, OH). The remainder of the sample was spun for 20 min at 10,000 rpm and 4°C to obtain platelet-poor plasma. The plasma was stored at −80°C until assayed.Assays.t-PA antigen and PAI-1 activity were measured using enzyme linked immunosorbency assays (ELISA) (American Diagnostica, Inc., Greenwich, CT). t-PA activity was measured using an amidolytic activity assay (Biopool International, Ventura, CA). Postexercise values were corrected for plasma volume changes, which were calculated using hematocrits (23).Statistical analyses.Mean differences in t-PA activity, t-PA antigen, and PAI-1 activity at each time point were assessed using a repeated measures ANOVA. Post hoc means comparisons were performed by contrasting the one min postexercise value against all other time points (JMP statistical software, SAS Institute, Inc., Cary, NC). A priori statistical significance was set at P < 0.05. Effect sizes for power calculations were based on data from the first five subjects tested. Based on these data, it was determined that eight subjects would result in a power of 0.92 for tPA activity, 0.99 for tPA antigen, and 0.14 for PAI-1 activity. It was also determined that 37 subjects would be necessary to yield a power of 0.80 for PAI-1 activity.RESULTSExercise test results for all eight subjects are as follows (data listed as mean ± SD): V̇O2max = 52.2 ± 4.3 mL·kg−1·min−1, max HR = 198 ± 13 beats·min−1, RER = 1.17 ± 0.08, and blood [La−] = 8.81 ± 1.81 mmol·L−1. Figure 1 displays resting and postexercise t-PA activity. There was a 19-fold increase from preexercise (0.05 ± 0.06 IU·mL−1) to 1 min postexercise (9.84 ± 1.38 IU·mL−1). t-PA activity did not change significantly from 1 to 2 min postexercise (9.67 ± 1.49 IU·mL−1), but was significantly decreased at 4 min postexercise (7.96 ± 1.32 IU·mL−1) (P < 0.05) compared with the 1-min postexercise value.FIGURE 1—Mean ± SE of t-PA activity (IU·mL−1) levels from preexercise to 10 min postexercise. * Significantly different than 1 min postexercise (P < 0.05).As seen in Figure 2, there was a fivefold increase in t-PA antigen from preexercise (5.92 ± 0.98 ng·mL−1) to 1 min postexercise (30.70 ± 4.64 ng·mL−1). t-PA antigen remained elevated from 1 to 2 min postexercise (30.57 ± 4.47 ng·mL−1) and significantly decreased by 4 min postexercise (25.71 ± 4.35 ng·mL−1) (P < 0.05) compared with the 1 min postexercise value.FIGURE 2—Mean ± SE of t-PA antigen (ng·mL−1) levels from preexercise to 10 min postexercise. * Significantly different than 1 min postexercise (P < 0.05).PAI-1 activity (Fig. 3) significantly decreased from preexercise (11.16 ± 2.18 AU·mL−1) to 1 min postexercise (4.89 ± 1.61 AU·mL−1) (P < 0.05). No significant change was observed from 1 min postexercise to any other postexercise time point (P > 0.05).FIGURE 3—Mean ± SE of PAI-1 (AU·mL−1) activity levels from preexercise to 10 min postexercise.DISCUSSIONThe major finding of the present study was that plasma t-PA activity and antigen decrease significantly between 2 and 4 min after acute maximal exercise. Furthermore, PAI-1 levels remained unchanged for 10 min after exercise. This suggests that investigators evaluating the t-PA response to acute exercise should collect blood samples within 2 min after the cessation of exercise and that PAI-1 can be accurately determined as long as blood is collected within 10 min after acute exercise.The significant increase in t-PA with response to acute exercise is consistent with previous data (10,14,15,22). Large increases similar to those seen in the present study are not uncommon, as t-PA has been shown to increase 31-fold after a bout of exercise (20). Although previous investigations have not measured postexercise t-PA as frequently (every 2 min) as the present study, others have observed that t-PA decreases in a short period of time during recovery from acute exercise. Gunga et al. (12) obtained blood samples at 2 and 9 min postexercise and observed a large decrease in t-PA between those two time periods. Further, Davis et al. (5) observed a decrease in fibrinolytic activity, as assessed by clot lysis time within 5 min after acute exercise, as did Wheeler et al. (26), when comparing immediate and 8-min postexercise values. Taken together with these previous investigations of t-PA and global measures of fibrinolytic activity, the present data suggest that the decrease in t-PA during the postexercise period likely results in a general decrease in fibrinolytic activity within 4 min of exercise cessation.One possible explanation for the rapid decrease of t-PA levels after exercise is an increase in blood flow to the liver (25). The rapid liver uptake of t-PA after exercise is accomplished by the mannose receptor on endothelial liver cells and a low-density lipoprotein receptor-related protein known to be a hepatic receptor for both free t-PA and the t-PA/PAI-1 complex (16). Although hepatic clearance decreases during exercise, clearance rapidly returns to normal after exercise (7). Therefore, a sudden increase in liver blood flow could result in a rapid postexercise clearance of t-PA.Whereas active t-PA is cleared rapidly, there is a slower clearance rate for the t-PA/PAI-1 complex (2–4). Therefore, PAI-1 can decrease t-PA clearance by forming a complex to t-PA. However, if PAI-1 is decreased, as is the case after acute exercise, less t-PA and PAI-1 binding would occur allowing for a faster clearance rate of t-PA. Although speculative, this represents a potential way that the sustained decrease in postexercise PAI-1 activity contributed to the rapid decline in plasma t-PA during the postexercise period.Most prior studies observed significant decreases in PAI-1 in response to acute exercise (15,20,22,28,29). However, there do not appear to be any published studies that have evaluated the time course of PAI-1 changes during the postexercise period. Data from the present study show that, whereas PAI-1 activity decreases in response to acute exercise, the postexercise values remain unchanged for at least 10 min. This is a particularly interesting finding, as it could be expected that the rapid decrease in t-PA could have increased PAI-1 activity. The stable plasma PAI-1 activity during the postexercise period could be the result of increased activated protein C, which also binds and inactivates PAI-1 (18). However, this possibility is speculative, and warrants further investigation.This study indicates the importance of collecting blood samples within 2 min after acute exercise for accurate determination of plasma t-PA. However, certain limitations to this study exist. First, all subjects performed an acute bout of maximal exercise. Because t-PA and PAI-1 exercise responses are intensity-dependent, it is unknown if an identical postexercise response would be seen with lower-intensity exercise. Furthermore, the first postexercise blood sample was collected 1 min after cessation of exercise. It remains unknown whether changes in t-PA occur during the first minute of the postexercise period. However, because there was no change in t-PA or PAI-1 between 1 and 2 min postexercise, it is likely that there would also not be any significant changes during the first minute after exercise. Subjects in the present study were young, healthy untrained males. 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