Time course of sympathoadrenal adaptation to endurance exercise training in man.

Time course of sympathoadrenal to endurance exercise training

adaptation in man

W. W, WINDER, J. M. HAGBERG, R. C. HICKSON, A. A. EHSANI, AND J. A. McLANE Department of Preventive Medicine, Washington University St. Louis, Missouri 63110

W. W,, J. M. HAGBERG, R. C. HICKSON, A. A. J. A. MCLANE. Time course of sympathoadrenal aduptation to endurance exercise training in man. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 45(3): 370-374, 1978. -One possible reason for the lower exercise heart rate after endurance exercise training is that the sympathetic drive to the heart is reduced. We have studied the relationship between plasma catecholamines and heart rate during exercise in the course of a 7-wk training program. Six untrained subjects exercised vigorously (on bicycle ergometers and by running) 30-50 min/day for 7 wk. Prior to the beginning of training and at weekly intervals thereafter, participants were subjected to a 5-min strenuous bicycle ergometer test. In the test prior to training, plasma epinephrine increased to 0.5 ng/ ml and norepinephrine increased to 3.0 rig/ml. The major proportion of the training-induced decrement in catecholamine response was reached at the end of the 3rd wk when epinephrine increased to 0.17 rig/ml and norepinephrine increased to 1.5 rig/ml in response to the same test. Heart rate during exercise continued to decrease even after the catecholamine response had plateaued, implying that the reduced sympathetic response is not solely responsible for the reduced exercise heart rate. WINDER,

EHSANI,

AND

epinephrine;

norepinephrine;

heart rate; blood lactate

EFFECTS of endurance is that heart rate is lower during submaximal exercise (9, 21, 23). The mechanism of this effect, of training has not been clearly defined. Plasma catecholamines increase during exercise (5, 10, 13, 1517, 24) and the magnitude of the increase in plasma norepinephrine during exercise is less after training (5, 10, 17). Urinary excretion of catecholamines is also elevated following exercise (4, 20, 25). Reduced postexercise urinary catecholamine excretion has been reported in rats but not in humans after a period of training (4, 7, 11, 20). Thus, one possible reason for a training-induced reduction in exercise heart rate may be that sympathetic drive to the heart may be less after training (cf. Ref. 23). The effects on heart rate occur soon after start of an endurance-exercise training program (1). The purpose of this experiment was to determine the time course of the training-induced adaptation of the sympathoadrenal response to exercise and to correlate the change in plasma catecholamine response with the reduction in heart rate. ONE

OF

exercise

370

THE

WELL-DOCUMENTED

training

School

of Medicine,

METHODS

Training program. Six healthy male subjects, (ages 30 t 1 yr) participated in a 7-wk endurance training program. Four of the six subjects had participated in previous studies and were well accustomed to laboratory testing procedures. Subjects worked on the bicycle ergometer and ran on alternate days. The bicycle ergometer work consisted of six 5-min bouts of pedaling at work loads that initially elicited the subject’s maximal oxygen consumption (vo, max)by the end of each bout. The work intervals were separated by 2-min rest periods. On alternate days, subjects ran at a pace they could maintain for 40 min, (5-8 km). Two of the six subjects worked on the bicycle 6 days/wk instead of running on alternate days. All participants exercised 6 days/wk. Once established, daily work loads were kept constant for the first 4 wk of the study. At the end of 4 wk the capacity of the subjects to work was increased. The bicycle work loads were then increased to levels that again elicited Vo, max. Subjects were instructed to run at a more rapid pace on their running days. They then worked at these levels for the remaining 3 wk of the study. of maximal oxygen consumption .Determination wo 2max). Maximal oxygen consumption was determined on each subject prior to training and at the end of 7 wk of training as a measurement of the effectiveness of the program. Subjects worked on bicycle ergometers (Quinton Instruments, Seattle, Wash.) at increasing work loads until oxygen consumption plateaued as a function of work load. Expired air was collected in meteorological balloons and analyzed with a PerkinElmer mass spectrometer (Pomona, Calif.) Volumes were measured with an American gas meter (Warren E. Collins, Braintree, Mass.). Exercise tests. Prior to the beginning of training and at weekly intervals during the training participants were subjected to a 5-min bicycle ergometer test at approximately 95% of initial VoZ max. Work loads averaged 1,483 -t 83 kpm/min for this test. At the end of training, subjects were also tested at approximately 100% of their new vo, lllaX(1,920 t 80 kpmlmin). At least 20 min prior to these tests a catheter was inserted into an antecubital vein. The subject then rested in a supine position for 15 min, Blood samples (5 ml) were collected via the venous catheter immediately

00%8987/78/0000-0000$01.25

l

Copyright

0 1978 the American

Physiological

Society

Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on August 27, 2018. Copyright © 1978 American Physiological Society. All rights reserved.

SYMPATHOADRENAL

ADAPTATION

TO

371

TRAINING

prior to exercise during the last 10 s of the 5-min Catecholamine responses. Before training, resting exercise bout and 5-min postexercise. The preexercise levels of plasma catecholamines averaged 0.26 t 0.05 sample was taken with subjects in the supine position. rig/ml for norepinephrine and 0.08 t 0.02 rig/ml for The other two samples were taken with subjects sitting epinephrine. Resting catecholamines were not signifion the bicycle ergometer. Heart rate was determined by cantly altered by training. Plasma levels of epinephrine palpation. and norepinephrine were considerably lower during Processing of blood. For the catecholamine assays, exercise after 7 wk of training (Fig. 1 and Table 1). At 3.0 ml blood were added to a chilled tube containing 4.5 the same absolute work load, plasma epinephrine mg reduced glutathione, 0.1 mg pargyline, and 50 U showed very little increase in concentration during sodium heparin. For glucose and lactate assays, 0.2 ml exercise after training (Fig. 1)SPlasma norepinephrine blood was added to 1.0 ml 10% perchloric acid. All blood increased during exercise after training but only to half samples were kept ice cold and were centrifuged within the pretraining concentration (Fig. 1). When subjects lo-15 min after collection. Plasma and perchloric acid worked at a higher work load after training, norepiextracts were stored frozen at -2OOC until time of nephrine and epinephrine in blood increased to levels analysis. higher than pretraining values at lower work loads Assays. Plasma samples for catecholamines were (Table 1). stored frozen until the end of the study so that all A significant reduction in plasma catecholamines samples for each subject could be run in the same assay, during exercise was seen after 1 wk of training (Fig. 2). Plasma epinephrine and norepinephrine were deter- A continuation of training at the same intensity remined by the radiometric assay described by Cryer et sulted in additional decreases in the catecholamine al. (12). Catechol 0-methyltransferase was isolated response to exercise. The majority of the training-infrom rat liver by the method of Axelrod and Tomchick duced decrement in plasma epinephrine and norepi(2). S-adenosyl-[3H]methionine was obtained from New nephrine concentration had occurred by the end of the England Nuclear. Only the samples taken at the end of exercise were run in duplicate. The difference between 0 Pre -Training WREPINEPHRINE: duplicate samples within the same assay averaged 12 n 7 Wks Training 3 * 3% of the means for norepinephrine and 10 t 3% for epinephrine. The perchloric acid extracts were neutralized and analyzed for glucose (3) and lactate (14). RESULTS

Magnitude of training adaptation. VO, maxincreased from 3.46 2 0.21 to 4.23 t 0.26 l/min during the course of the training program. Heart rate at the end of the 5min exercise test was significantly lower after training (Fig. 1 and Table 1). Blood 1act at e was also much lower after training, particularly in the postexercise period (Table 1).

Om6

z a

EPINEPHRINE

0.4

= 0.2

h TABLE

1. Effect of training P&raining

5 Min postexercise Plasma NE, ng/ ml Plasma E, rig/ml Heart rate, beats/ mm Blood lactate, mM Values epinephrine.

P < 0.05.

are

‘ffa

End of Training

1,483 k 83 kpmlmin

End of 5-min exercise Plasma NE, ng/ ml Plasma E, ngiml Heart rate, beats/ min Blood lactate, mM

g

on responses to exercise

1,483 2 83 kpml min

1

1,920 * 80 kpml min

HEART 2.95

5 0.32

1.60

k O-09*

4.04

f

0.53 187

2 0.13 + 4

0.14

k d.03":

1.24 171

k 0.19* c 3%

7.1 * 1.0

3.8

9.5

k 0.6

151 4 4* -t- 0.3*

0.71 * 0.12*

1.82 2 0.20

0.17 116

0.09 * 0.031" 83 * 5%

0.38 k o-07* 98 k 4*

11.5

-+ 0.04 k 6

k 1.1

means -+ * Significantly

SE. different

4.6

2 0.7*

NE, from

12.6

k 0.8

norepinephrine; E, pretraining response,

RATE

$60 s

0.67*

1.90 2 0.26

I

2120

a M

80

b EXERCISE

1 5

5

0 TIME

POST

(Mid

1. Effect of 7 wk training on plasma catecholamine, blood lactate, and heart rate resx>onses to a 5-min exercise bout at 1.483 + 83 kp&min. With exception of preexercise values for lactate and catecholamines, all training values are significantly different from pretraining values, P < 0.05. FIG.


372

WINDER

ET

AL.

catechol .amine response; that is, heart rate response to exerme was still decreasing even when plasma catecholamine response had plateaued (Fig. 2).At the end of training when subjects worked at the higher work load heart rate was significantly lower, even though plasma catecholamines were higher than pretraining test values at the lower work load (Table 1) . DISCUSSION

0.6

EPINEPHRI

NE

1 ,*

BLOOD

1

1

1

1

1

1

LACTATE

1

2 WEEK

3 CF

4

5

6

7

TRAINING

FIG. 2. Time course of effect of training on plasma catecholamine, blood lactate, and heart rate responses to a 5-min exercise bout at 1,483 * 83 kpmimin. All training values are significantly different from pretraining values, P < 0.05.

3rd wk of training. Even though the intensity of exercise during daily training sessionswas increased at the end of the 4th wk, no further significant changes were seen in the catecholamine response to exercise at the same absolute work load. Blood glucose and lactate. Blood glucose was not significantly affected by these 5-min exercise bouts either before or after training. Prior to training blood lactate increased during exercise to 7.10 2 0.95 pmol/ ml and then continued to increase to 11.5 t 1.14 pmol/ ml 5 min after exercise. After training lactate increased to 3.8 t 0.3 pmol/ml at the end of exercise and then remained approximately the same during the postexercise period (4.6 t 0.7 pmol/ml). The decline in blood lactate response to exercise did not correspond closely to th .e decline in catecholamin .e response* As can be seen in Fig. 2, postexercise blood lactate continued to decline whereas catecholamines were not influenced by additional training. Heart rate. The heart rate respon se to exercise was dramatically affected by training, Training caused a rapid decline in the exercise heart rate for the first 2 wk of training. Two weeks of additional training at the same intensity did not significantly lower heart rate (Fig. 2). When the intensity of training was increased at the end of the 4th wk, an additional decrement in heart rate response to exercise was observed. This decrement was-not accompanied by a decreased plasma

The training program used in this study was designed to maintain the stimulus for adaptation constant for the first 4 wk of the study. Subjects were extremely uncomfortable during the first few training sessions, but by the end of the 3rd wk these training work loads were quite tolerable. If a progressive training program had been used, a different time course would probably have been observed. The rapidity of the adaptation to a progressive program probably depends on the intensity and duration of initial work bouts and on the rate of progression to heavier work loads. We were surprised by the observation that after the rapid initial adaptation during the first 3 wk no further decline in catecholamine response was noted, even though intensity of the daily work bouts was increased at the end of the 4th wk. The increment in intensity of work at this time was relatively small in relation to the increase in daily work when subjects began training. It is likely that a further decline in catecholamine response to this test would be seen if subjects trained for longer periods of time each day, perhaps in two sessions. Our observation that heart rate during exercise continued to decline after the catecholamine response had plateaued implies that adaptations other than the decreased catecholamines are responsible in part for the lower heart rate of trained individuals during submaxima1 exercise. The training-induced reduction in heart rate after the 3rd wk of training in this study could be attributed to increased parasympathetic tone, to reduced sensitivity of the heart to catecholamines, or to intrinsic adaptations+ These mechanisms have also been postulated to contribute to the lower heart rate response to exercise (cf. Ref. 23). Our results imply that these other changes may occur at a different time in the course of training than does the sympathoadrenal adaptation. It is also possible that a local continued decrease in release of norepinephrine from cardioaccelerator nerves is not detectable in peripheral venous plasma. Our observation that posttraining heart rate is lower even when catecholamine levels are higher during and after strenous exercise (Table 1) implies that the heart is becoming less sensitive to sympathet ic stimulation. It is not possible to determine from our data whether this reduced “responsiveness” is due to increased parasympathetic activity or to a reduction in the sensitivity or number of adrenergic receptors in the heart. The precise mechanism for the training-induced decline in catecholamine response to exercise is not known at the present time. Christensen et al. recently reported that plasma epinephrine correlates inversely with blood


SYMPATHOADRENAL

ADAPTATION

TO

373

TRAINING

glucose and that plasma norepinephrine correlates inversely with oxygen saturation in pulmonary artery blood during exercise (8). Blood glucose was not altered during the exercise test used in this study. Blood glucose levels undoubtedly play a role in determining the adrenal medullary secretion rate during long-term exercise when blood glucose decreases but not during short-term high-intensity exercise. With regard to the pulmonary artery oxygen saturation, trained individuals have increased arteriovenous 0, differences across working muscles during maximal exercise (cf. Refs. 18, 21, 23). It is unlikely that oxygen saturation in the pulmonary artery is higher during exercise after training. The reduction in exercise heart rate and probably the reduced catecholamine response are at least partially dependent on intramuscular adaptations. The heart rate reduction resulting from arm training does not carry over to exercise performed with nontrained leg muscles (cf. Ref. 9). Saltin et al. in their one-leg training experiments, also demonstrated that the lowered submaximal exercise heart rate response was restricted to exercise with the trained leg (22). It is conceivable that feedback from the muscle via afferent nerves determines the magnitude of the sympathoadrenal response to exercise (cf. Refs. 9, 22). Stimulation of the central cut end of nerves of hindlimb muscle of the dog causes cardioacceleration (N), thus indicating the presence of a neural pathway for such a reflex. The intramuscular adaptations to training (i.e., increased myoglobin and increased number of mitochondria (18)) may cause a change in the metabolic and ionic milieu

at the sensory receptor sites in the muscle, thus reducing afferent nerve impulses and consequently reducing adrenergic output by the autonomic nervous system. In rats, cytochrome c and other mitochondrial proteins in muscle increase with a half time of approximately 7 days in response to training 100 min/day on a motordriven treadmill (6). The time course of the intramuscular adaptation is probably very similar to the time course of the sympathoadrenal adaptation, but additional studies will be required to establish this relationship in the same species. In summary, we have demonstrated in a longitudinal study of human subjects that the plasma catecholamine response to exercise is less after training. The major component of this adaptation occurred within 3 wk after the start of training. The exercise heart rate continued to decline after the catecholamine response had plateaued. We thank the subjects who were splendidly cooperative during the course of this time-consuming study. We are indebted to Dr. John 0. Holloszy for his constructive suggestions, to Ms. Sandy Zigler for typing the manuscript, and to Mrs. May Chen and Mrs. Mary Van Auken for skillful technical assistance. R. C. Hickson and 5. A. McLane were postdoctoral research trainees supported by National Institutes of Health Training Grant AM-05341. J. M. Hagberg was a postdoctoral research trainee supported by National Institutes of Health Training Grant HL07081. This study was supported in part by a National Institutes of Health Biomedical Research Support Grant to Washington University Medical School. Received

3 January

1978; accepted

in final

form

25 April

1978.

REFERENCES 1. ASTRAND, P.-O., AND K. RODAHL. Textbook of Work PhysioZogy. New York: McGraw, 1970, p. 359. 2. AXELROD, J., AND R. TOMCHICK. Enzymatic O-methylation of epinephrine and other catechols. J. BioZ. Chem. 233: 702-705, 1958. 3. BERGMEYER, H. U., E. BERNT, F. SCHMIDT, AND H. STORK. Dglucose. Determination with hexokinase and glucose-6-phosphate dehydrogenase. In: Methods of Enzymatic Analysis (2nd ed.), edited by H, U. Bergmeyer. New York & London: Academic, 1974, p. 1196-1201. 4. BERNET, F., AND J. DENIMAL. Evolution of the sympathicoadrenal response to exercise during physical training in the rat. In: Metabolic Adaptation to Prolonged Physical Exercise, edited by H. Howald and J. R. Poortmans. Basal: Birkhaeuser, 1975, p. 326-332. 5. BLOOM, S. R., R. H. JOHNSON, D. M, PARK, M. J. RENNIE, AND W. R. SULAIMAN. Differences in the metabolic and hormonal response to exercise between racing cyclists and untrained individuals. J. Physiol. London 258: 1-18, 1976. 6. BOOTH, F. Effects of endurance exercise on cytochrome c turnover in skeletal muscle. Ann. iVY Acad. Sci. 301: 431-439, 1977. 7. BRUNDIN, T., AND C. CERNIGLIARO. The effect of physical training on the sympathoadrenal response to exercise. Stand. J. Clin. Lab. Invest. 35: 525-530, 1975. 8. CHRISTENSEN, J. J., H. GALBO, J. F. HANSEN, B. HESSE, AND J. 5. HOLST, Plasma adrenaline correlates to blood glucose and plasma noradrenaline to pulmonary artery oxygen saturation during exercise both before and after propranolol (Abstract). Diabetologia 13(4): 387, 1977. 9. CLAUSEN, J. P. Effect of physical training on cardiovascular adjustments to exercise in man. Physiol. Rev. 57: 779-815, 1977. 10. COWSINEAW, D., R. J. FERGUSON, J. DE CHAMPLAIN, P. GAUTHIER, Pa COTE, AND M. BOURASSA. Catecholamines in coronary sinus during exercise in man before and after training. J. A&.

Physiol.: Respirat. Environ. Exercise PhysioZ. 43: 801-806, 1977. 11. CRONAN, T. L., AND E, T. HOWLEY. The effect of training on epinephrine and norepinephrine excretion. Med. Sci. Sports 6: 122-125, 1974. 12. CRYER, I? E., J. V. SANTIAGO, AND S. SHAH. Measurement of norepinephrine and epinephrine in small volumes of human plasma by a single isotope derivative method: response to the upright posture. J. CZin. Endocrinol. Metab. 39: 1025-1029, 1974. 13. GALBO, H., J. J. HOLST, AND N. J. CHRISTENSEN. Glucagon and catecholamine responses to graded and prolonged exercise in man, J, Appl. Physiol. 38: 70-76, 1975. 14. GUTMANN, I., ANI) A. W. WAHLEFELD. L-[+]Lactate. Determination with lactate dehydrogenase and NAD. In: Methods of Enzymatic Analysis (2nd ed.), edited by H. U. Bergmeyer. New York & London: Academic, 1974, p. 1464-1.468. 15. HAGGENDAL, J., L. H. HARTLEY, AND B. SALTIN. Arterial noradrenaline concentration during exercise in relationship to the relative work levels, Stand. J. CZin. Lab. Invest. 26: 337-342, 1970. 16. HARTLEY, L, H., J. W. MASON, R. P. HOGAN, L. G. JONES, T. A, KOTCHEN, E. H. MOUGEY, F. E. WHERRY, L. L. PENNINGTON, AND P. T. RICKETTS. Multiple hormonal responses to graded exercise in relation to physical training. J. AppZ* Physiol. 33: 602-606, 1972. 17. HARTLEY, L. H., J. W. MASON, R. P. HOGAN, L. G. JONES, T. A. KOTCHEN, E. H. MOUGEY, F. E. WHERRY, L. L. PENNINGTON, AND P. T. RICKETTS. Multiple hormonal responses to prolonged exercise in relation to physical training. J. Appl. Physiol. 33: 607-610, 1972, 18. HOLLOSZY, J. O., AND F. W. BOOTH. Biochemical adaptations to endurance exercise in muscle. Ann. Rev. Physiol. 38: 273-291, 1976. 19. MITCHELL, J. H., W. C. REARDON, D, I. MCCLOSKEY, AND K. WILDENTHAL. Possible role of muscle receptors in the cardiovas-


374 cular responses to exercise. Ann. NY Acad. Sci. 301: 232-242, 1977. 20. OSTMAN, I., N. 0. SJ~STRAND, AND G. SWEDIN. Cardiac noradrenaline turnover and urinary catecholamine excretion in trained and untrained rats during rest and exercise. Acta PhysioZ. Stand. 86: 299-308, 1972. 21. ROWELL, L. B. Human cardiovascular adjustments to exercise and thermal stress. Physiol. Rev. 54: 75-159, 1974. 22. SALTIN, B. The interplay between peripheral and central factors

WINDER

ET

AL.

in the adaptive response to exercise and training. Ann. NY Acad. Sci. 301: 224-231, 1977. 23. SCHEUER, J., AND C. M. TIPTON. Cardiovascular adaptations to physical training. Ann. Rev. Physiol. 39: 221-251, 1977. 24. VENDSALU, A. Studies on adrenaline and noradrenaline in human plasma. Acta Physiol. Stand. Suppl. 173: l-123, 1960. 25. VON EULER, U. S. Sympatho-adrenal activity in physical exercise. Med. Sci. Sports 6: 165-173, 1974.


Nutrition and the adaptation to endurance training.

Time course of muscle adaptation after high force eccentric exercise.

Mitochondrial enzymatic adaptation of skeletal muscle to endurance training.

Adaptation of the rat myocardium to endurance training.

Diaphragmatic fiber type specific adaptation to endurance exercise.

Adaptation of protein metabolism to endurance training. Increased amino acid oxidation in response to training.

Time-course of the antihypertensive and autonomic effects of regular endurance exercise in human subjects.

Weekly Time Course of Neuro-Muscular Adaptation to Intensive Strength Training.

Endurance training of older men: responses to submaximal exercise.

Beta-endorphin time course response to intensity of exercise: effect of training status.

Strength training prior to endurance exercise: impact on the neuromuscular system, endurance performance and cardiorespiratory responses.

Adaptation of endurance training with a reduced breathing frequency.

The course of labor after endurance exercise during pregnancy.

Adaptation of mitochondrial ATP production in human skeletal muscle to endurance training and detraining.

Echocardiographic assessment of right ventricle adaptation to endurance training in young rowers - speckle tracking echocardiography.

Immune adaptation to chronic intense exercise training: new microarray evidence.

Exercise training-induced coronary vascular adaptation.

PBMCs express a transcriptome signature predictor of oxygen uptake responsiveness to endurance exercise training in men.

Pulmonary adaptation to exercise: effects of exercise type and duration, chronic hypoxia and physical training.

Biventricular response of the heart to endurance exercise training in previously untrained subjects.

Skeletal muscle metabolic adaptations to endurance exercise training are attainable in mice with simvastatin treatment.

Acute and Post-Exercise Physiological Responses to High-Intensity Interval Training in Endurance and Sprint Athletes.

Twelve Weeks of Sprint Interval Training Improves Indices of Cardiometabolic Health Similar to Traditional Endurance Training despite a Five-Fold Lower Exercise Volume and Time Commitment.

The miRNA plasma signature in response to acute aerobic exercise and endurance training.