INTRODUCTION

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STRENUOUS EXERCISE RESULTS in a massive activation of the sympathetic nervous system (SNS) (8-10, 13, 18, 24). This increase in catecholamine production plays a major role in mediating the cardiovascular and metabolic responses to exercise that are responsible for increasing the supply of oxygen and fuel to the working muscles (2, 17, 20, 27). The activation of the SNS by exercise can be monitored by measuring the increase in plasma norepinephrine (NE) due to spillover at the nerve endings, as well as by monitoring the increase in plasma epinephrine (Epi) due to increased secretion by the adrenal medullas (23). In addition to increased NE release, a decrease in clearance appears to make a small contribution to the increase in plasma NE during exercise (10, 13, 15).

A major factor that determines the magnitude of the SNS response is the relative stress of the exercise (4). For the aerobic-endurance type of exercise, a good measure of relative intensity appears to be the percentage of maximal oxygen consumption (O_{2 max}) that the exercise elicits. It is well documented that plasma NE and Epi concentrations increase as relative exercise intensity is increased (5, 6, 18, 28, 29). It is, therefore, not surprising that strenuous aerobic exercise training that induces a large increase in O_{2 max} brings about a blunting of the catecholamine response to exercise of the same absolute intensity, which represents a smaller percentage of the new, higher O_{2 max}.

Whereas a lower plasma NE response to exercise of the same absolute intensity after training is well documented (5, 6, 18, 28, 29), it is still not clear what effect training has on the plasma NE response to exercise of the same relative intensity. Although the question has been addressed by a number of investigators, the results have been inconsistent, with some reporting no change (18, 29) and others reporting a decreased response (8), whereas still others found an increased NE response (6, 28). In these studies, different relative intensities were investigated, which may have contributed to the conflicting results. The present study was undertaken to reevaluate the effect of endurance exercise training on the plasma catecholamine response to exercise at the same percentage of O_{2 max} over a wide range of intensities in an attempt to explain the discrepant results of previous studies.

	METHODS

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Subjects. Nine healthy untrained subjects (6 women and 3 men) agreed to participate in the present study. Descriptive data for the subjects are presented in Table 1. The subjects provided written informed consent to participate in this study, which was approved by the Human Studies Committee of the Washington University School of Medicine.

Maximal exercise testing. O_{2 max} was measured during a continuous treadmill test to exhaustion. The treadmill speed was adjusted during the warm-up period to elicit a heart rate that was ~70% of age-predicted maximal heart rate. The speed of the treadmill was held constant during the test (134-214 m/min), and the grade of the treadmill was increased 2% every 2 min to an end point of exhaustion. Expired air was collected and analyzed breath by breath with an automated online system (Max-1, Physio-Dyne Instrument, Farmingdale, NY). At least two of the following criteria were required for an acceptable O_{2 max} test: plateau in oxygen consumption with increasing work rate, heart rate within 10 beats/min of age-predicted maximal heart rate, and a respiratory exchange ratio exceeding 1.10. O_{2 max} was reassessed after a 10-wk training program. Body composition was estimated from skinfold measurements before and after training (12, 25).

Submaximal exercise testing. The subjects reported to the laboratory at least 3-h postabsorptive to perform the submaximal exercise tests. A polyethylene catheter was inserted into an arm vein for blood sampling and was kept patent with saline. The response to treadmill exercise was evaluated during two randomized tests separated by 48 h. One series of tests consisted of 15 min of walking or running on the treadmill at each of three exercise intensities (60, 70, and 80% of O_{2 max}). Thirty minutes of seated rest separated the exercise bouts. The other series of tests consisted of walking or running at each of three exercise intensities (65, 75, and 85% of O_{2 max}). A baseline blood sample was obtained after 30 min of supine rest in a quiet room (rest). The exercise blood samples were obtained during the last minute of each 15-min exercise bout. The 15-min-long exercise bouts began with 5 min of warm-up during which the treadmill speed was increased progressively until the appropriate oxygen consumption was reached. The subject continued to exercise at the appropriate intensity for the remaining 10 min of the exercise bout. Oxygen consumption was measured throughout the exercise bouts to ensure that treadmill speed was appropriate to elicit the desired exercise intensity (i.e., 60-85% of O_{2 max}). Heart rate was also measured throughout the exercise bouts with radiotelemetry (Polar Vantage XL, Stamford, CT). The oxygen consumption and heart rate values reported are the average of those measured during the last 3 min of each exercise bout. The response to submaximal treadmill exercise was reevaluated at the same relative exercise intensities (i.e., 60-85% of trained O_{2 max}) after a 10-wk training program. Subjects abstained from exercise for 24 h before each submaximal exercise test series. The tests were performed at the same time of the day.

Exercise training. The 10-wk training program consisted of high-intensity cycle ergometer exercise 3 days/wk and continuous running 3 days/wk (11). The cycle ergometer exercise for the first 2 wk consisted of four 5-min exercise bouts at ~90-100% of O_{2 max}. Two minutes of recovery separated the exercise bouts during which the subject cycled at ~50-100 W. After the second week, the cycling protocol was increased to five 5-min exercise bouts and was kept at that level for the remaining 8 wk. The running exercise consisted of continuous running for 30 min/day for the first week, 35 min/day for the second week, and 40 min/day for the remaining 8 wk. Subjects were encouraged to run at as fast a pace as they could maintain during the exercise sessions. Cycling power output was adjusted throughout the training protocol to keep pace with the subject's increasing maximal exercise capacity.

Blood analysis. Blood samples for catecholamine determination were put in chilled tubes containing reduced glutathione and EGTA. Samples were subjected to centrifugation (15 min at 2,000 g), and the supernatant was collected and stored at 80°C for subsequent analysis. A single-isotope derivative (radioenzymatic) method was used for the determination of plasma NE and Epi concentrations (22).

Statistical analysis. Two-way repeated measures analyses of variance were performed to analyze differences in heart rates and plasma NE and Epi concentrations before and after training. If significant interactions were found, paired t-tests were used for further analyses. Paired t-tests were also used to analyze differences between plasma NE and Epi concentrations before and after training at the same absolute exercise intensities. Statistical significance for all statistical tests was accepted at the P < 0.05 alpha level.

	RESULTS

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Training effects. The average increase in O_{2 max} in response to 10 wk of exercise training was ~20% (untrained: 39.2 ± 7.7 ml · kg1 · min¹, trained: 46.9 ± 8.1 ml · kg¹ · min¹; P < 0.05) Body weight and percent body fat were not altered by exercise training. Descriptive data for the subjects are presented in Table 1.

Submaximal exercise response. Each subject exercised at work rates calculated to be 60, 65, 70, 75, 80, and 85% of O_{2 max} before and after training. Measured oxygen uptakes, expressed as a percentage of O_{2 max}, are presented in Table 2. These data show that the subjects were at the desired percentage of O_{2 max} both before and after training.

Plasma NE response to exercise at the same relative intensity. Plasma NE concentrations increased progressively as exercise intensity increased from 60 to 85% of O_{2 max} both before and after training (Fig. 1). Plasma NE concentrations at rest and at 60% of O_{2 max} were not significantly different after, compared with before, exercise training. Plasma NE concentrations were significantly higher in the trained compared with the untrained state at exercise intensities of 65-85% of O_{2 max}.

View larger version (17K): [in this window] [in a new window]   Fig. 1.   Plasma norepinephrine (NE) concentrations at rest and after 15 min of exercise at the same relative exercise intensity before and after 10 wk of endurance exercise training. O2 max, maximal O2 uptake. Values are means ± SE for 9 subjects. * Untrained vs. trained state, P < 0.05.

Plasma Epi response to exercise at the same relative intensity. Plasma Epi concentrations increased as exercise intensity increased from 60 to 85% of O_{2 max} both before and after training (Fig. 2). However, there was no significant difference in the magnitude of the Epi response in the trained compared with the untrained state, although there was a tendency for the increase to be greater at the two highest work rates after training.

View larger version (16K): [in this window] [in a new window]   Fig. 2.   Plasma epinephrine (Epi) concentrations at rest and after 15 min of exercise at the same relative exercise intensity before and after 10 wk of endurance exercise training. Values are means ± SE for 9 subjects.

Plasma NE and Epi responses at the same absolute work rate. Certain subjects had some work rates after training that corresponded to work rates before training (i.e., same absolute oxygen uptake). For these cases, the catecholamine response was compared at these work rates to determine the catecholamine response at the same absolute exercise intensity before and after training. Plasma NE concentrations during exercise at the same absolute work rates were significantly lower after training (956 ± 170 pg/ml) compared with before training (1,264 ± 160 pg/ml). Plasma Epi concentrations during exercise at the same absolute work rate were significantly lower after training (76 ± 9 pg/ml) compared with before training (146 ± 26 pg/ml).

Heart rate response to exercise at the same relative intensity. Heart rates were not significantly different at the same relative exercise intensity before and after training (Fig. 3).

View larger version (17K): [in this window] [in a new window]   Fig. 3.   Heart rates after 15 min of exercise at the same relative exercise intensity before and after 10 wk of endurance exercise training. Values are means ± SE for 9 subjects.

	DISCUSSION

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The present results clearly show that the plasma NE response to exercise at the same percentage of O_{2 max} is higher in the trained compared with the untrained state at work rates requiring 65-85% of O_{2 max}. This finding demonstrates that not only relative, but also absolute, exercise intensity plays a major role in determining the SNS response to exercise. That absolute work rate is important in regulating the catecholamine response to exercise should not come as a surprise, because the SNS response is one of the factors involved in adjusting the physiological and metabolic responses to the energy requirements of the working muscles (2, 17, 20, 27). The role of the absolute, compared with the relative, exercise intensity can be illustrated by a comparison of individuals who differ markedly in their O_{2 max}. When two individuals of the same size, one with a O_{2 max} of 60 ml · kg¹ · min¹ and the other with a O_{2 max} of 30 ml · kg¹ · min¹, both exercise at 75% of O_{2 max}, the working muscles of the subject with a O_{2 max} of 60 ml · kg¹ · min¹ require twofold more substrate and oxygen than do those of the individual with a O_{2 max} of 30 ml · kg¹ · min¹. Clearly, stimulation of glycogenolysis, lipolysis, and cardiovascular function must be greater to make possible exercise requiring 45 ml · kg¹ · min¹ (i.e., 75% of a O_{2 max} of 60 ml · kg¹ · min¹) than for exercise requiring 22.5 ml · kg¹ · min¹ (i.e., 75% of a O_{2 max} of 30 ml · kg¹ · min¹).

While the need for greater SNS activation at higher absolute exercise intensities seems obvious from this example, the mechanism(s) by which the greater SNS activation is mediated are still somewhat speculative. One mechanism that is thought to be involved in mediating the SNS response to exercise is stimulation of the arterial baroreceptors (19, 20). This suggests the following likely scenario. During exercise, the vascular bed in the working muscles dilates, resulting in a decrease in peripheral resistance and an activation of the baroreceptors. Activation of the arterial baroreceptors results in increased SNS activity, which in turn causes vasoconstriction of other vascular beds, thus maintaining blood pressure. The higher the absolute work rate, the greater the decrease in vascular resistance in the working muscles, the activation of the baroreceptors, and the stimulation of the SNS.

A second possible mechanism involves reflex sympathetic activation via muscle afferents. This reflex is thought to be mediated by stimulation of mechanoreceptors and chemosensitive nerve endings in the contracting muscles, which results in activation of the SNS via unmyelinated and thinly myelinated nerve fibers (1, 16, 20, 26). The disturbance in chemical homeostasis in muscle is largely a function of relative, rather than absolute, exercise intensity. Therefore, greater stimulation of the SNS via this mechanism at the same relative, but higher absolute, exercise intensities would probably have to be mediated by recruitment of a larger mass of skeletal muscle resulting in stimulation of more afferent nerves, rather than by more intense stimulation of the same afferents. That muscle mass plays an important role in determining the catecholamine response to exercise has been demonstrated by Seals (21) and Lewis et al. (14). These investigators found that the increase in plasma NE was a function of the amount of muscle recruited.

It is well documented that in humans the plasma Epi response to exercise is small compared with that of NE. A massive increase in plasma Epi occurs only when exercise results in development of hypoglycemia (3). The present finding that the increases in plasma Epi were similar at the same relative exercise intensities before and after training (except, perhaps, above 75% of O_{2 max}) provides further evidence that secretion of Epi by the adrenals is not regulated in parallel with NE release by the sympathetic nerve endings.

Our finding that heart rate was similar at the same relative work rate before and after training confirms the results of previous studies (6, 29). The finding that heart rate was not increased, despite increased SNS activity, as reflected in higher plasma NE levels, provides evidence for a decreased sensitivity to chronotropic stimulation. A possible explanation for this finding is provided by a study showing a decrease in -receptor number in the atria of minipigs that underwent exercise training (7).

With regard to the discrepancies between the results of previous studies, the finding of unchanged or blunted NE responses to exercise of the same relative intensity in the untrained and trained states may be explained by several factors. In a study by Winder et al. (29) in which the NE response at the same relative work rate was the same before and after training, the exercise intensity was only 62% of O_{2 max}. At such a low exercise stress, the catecholamine response is minimal and consequently not significantly different in the trained and untrained states (see Fig. 1). In a study by Peronnet et al. (18), low exercise intensity may also have played a role in the lack of significant differences in NE response post- compared with pretraining. However, it is not known at what percentage of O_{2 max} the subjects were exercising, because the exercise intensity was expressed in terms of maximal heart rate (work rate resulting in 70% of maximal heart rate). Although Peronnet et al. reported that training had no significant effect on NE response, it is of interest that NE concentration was 26% higher after training. The finding of Hartley et al. (8) of a smaller NE response at 75 and 98% of O_{2 max} after exercise training that increased O_{2 max} by 14% cannot be explained in the context of the present results.

In conclusion, the results of this study show that the plasma NE response to exercise that requires 65-85% of O_{2 max} is significantly higher after endurance exercise training that induces a large increase in O_{2 max}. We think it is probable that this greater NE response is mediated by recruitment of a larger muscle mass during exercise of the same relative, i.e., higher absolute, work rate after training.