Plasma catecholamine responses to exercise after training with P-adrenergic blockade EUGENE VICTORIA
E. WOLFEL, WILLIAM R. HIATT, H. L. BRAMMELL, TRAVIS, AND LAWRENCE D. HORWITZ
Divisions of Cardiology and General Internal Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262 WOLFEL, EUGENE E., WILLIAM VICTORIA TRAVIS, AND LAWRENCE
R. HIATT, H. L. BRAMMELL, D. HORWITZ. Plasma catecholamine responses to exercise after training with ,8-adrenergic blockade. J. Appl. Physiol. 68(2): 586-593, 1990.-Exercise training has been shown to decrease plasma norepinephrine (NE) and epinephrine (EPI) levels during absolute levels of submaximal exercise, which may reflect alterations in sympathetic tone as a result of training. To determine if ,&adrenergic blockade altered these changes in the plasma concentration of catecholamines with exercise conditioning, we studied the effects of P-adrenergic blockade on NE and EPI at rest and during exercise in 24 healthy, male subjects after a 6-wk exercise training program. The subjects were randomized to placebo (P), atenolol 50 mg twice daily (A), and nadolol 40 mg twice daily (N). There were no changes in resting NE and EPI compared with pretraining values in any subject group. During the same absolute level of submaximal exercise NE decreased in P and A but was unchanged in N, whereas EPI decreased only in P. At maximal exercise all three groups developed significant increases in NE after training that paralleled increases in systolic blood pressure. EPI at maximal exercise increased after training with N but was unchanged with P or A. These training-induced changes in plasma catecholamine levels were masked or blunted when the A and N groups were studied while still on medication after training. Thus ,&adrenergic blockade has important effects on adaptations of the sympathetic nervous system to training, especially during submaximal exercise. exercise training;
,8-adrenergic
antagonist
NERVOUS system activity plays an imporrole in both the hemodynamic and metabolic changes that occur with exercise (2). Resting plasma catecholamine levels, particularly norepinephrine, have served as indicators of the degree of sympathetic activation in normal healthy individuals (4), hypertensive patients (l3), and patients with cardiac disease (14). Exercise training results in a reduction in sympathetic tone, and decreases in plasma norepinephrine levels during exercise have been reported in both healthy individuals and cardiac patients after training (3, 8, 27). Although plasma levels reflect both the release and uptake of catecholamines, they seem to parallel the changes in turnover seen with exercise training (20). Thus plasma catecholamines can serve as markers for changes in sympathetic activity that occur with training. ,6-Adrenergic blockade has been shown to alter both SYMPATHETIC
tant
586
0161-7567/90
$1.50 Copyright
the hemodynamic and metabolic changes that occur with exercise (11, 32). During acute exercise several studies have shown reductions in maximal O2 consumption . (9), and (VO 2 max) (35, 38), exercise hemodynamics plasma levels of free fatty acids, glucose, and lactate (22) with ,&adrenergic blockade. The metabolic effects have been shown to be more pronounced with blockade of p2adrenergic receptors (18, 24). Measurements of plasma catecholamines during exercise with both selective and nonselective ,&adrenergic blockade have shown variable results with either no change (31) or an increase at rest and during exercise (6) compared with placebo. The importance of sympathetic stimulation during exercise training is somewhat unclear. Animal experiments have shown training effects from chronic infusions of sympathetic agonists (21) and reductions in training effects after P-adrenergic blockade (17), suggesting that some level of sympathetic stimulation is necessary for exercise training to occur. Some studies of human subjects with ,6-adrenergic blockade during training have reported attenuation of training effects (23, 28, 39), whereas in others unaltered conditioning effects were noted (25, 30, 34, 37). We sought to characterize the interaction between the sympathetic nervous system and exercise conditioning by measuring plasma catecholamine levels in healthy, young men who underwent an intense training regimen, randomized among groups with intact sympathetic control (placebo), cardioselective P-adrenergic blockade (atenolol), and nonselective ,6-adrenergic blockade (nadolol). We hypothesized that ,6-adrenergic blockade would attenuate the responses to an aerobic training program through alterations in the sympathetic nervous system and that plasma catecholamine levels would reflect these alterations. METHODS
Study design. Twenty-four healthy, untrained men, aged 21-35 yr, participated in the study. Written consent was obtained from each subject, and the project was approved by the Human Subjects Committee of the University of Colorado Health Sciences Center. All subjects underwent an initial maximal treadmill test before entry into the study for familiarization with the treadmill protocol. The subjects then underwent a series of graded, maximal treadmill tests as previously described (39).
0 1990 the American
Physiological
Society
Downloaded from www.physiology.org/journal/jappl at Glasgow Univ Lib (130.209.006.061) on February 13, 2019.
PLASMA
CATECHOLAMINES
AND
Initial testing (test I) was performed before exercise training or drug dosing. Subjects were then stratified by Tjo2 maxinto matched trios and randomized into placebo, selective (atenolol), or nonselective (nadolol) ,&-adrenergic blockade groups. Nadolol was prescribed at a dose of 40 mg twice a day and atenolol as 50 mg twice a day. The investigators and technical staff directly involved in testing or exercise training were blinded as to treatment. The degree of ,&-adrenergic blockade was assessed by the reduction in heart rate at maximal exercise on a treadmill test performed 5 days after the initiation of drug therapy (test 11). ,&-Adrenergic blockade was determined by the change in calf vascular resistance during an epinephrine infusion before and after drug administration as previously described (19). The vascular response to epinephrine was quite different between atenolol and nadolol with a marked increase in vascular resistance with nadolol and vasodilation with atenolol. The subjects then underwent a 6-wk exercise program of heart rate-monitored circuit training consisting of 50 min of treadmill walking, stationary cycling, and step walking three times a week and a 40-min run twice a week. All subjects trained at >85% of their maximal heart rate attained during test 11, which corresponded to 80% of their entry Tjozmax on drug or placebo. The details of the training regimen and the monitoring of compliance are described in a prior report (39). At the end of the 6th wk of training, another treadmill test was performed while the subjects were still taking medication (test 111). All drugs were discontinued while the subjects continued to exercise for 2 more days. A final treadmill test was performed 4-6 days after discontinuation of all drugs (test IV). Tread&I protocol. Each subject fasted at least 4 h before testing. A 20-gauge catheter was inserted in a retrograde fashion into a vein draining the dorsum of the hand, after which the subject rested supine in a quiet room for 30 min. Heart rate and blood pressure were then recorded, and a blood sample was withdrawn for plasma catecholamine analysis. The hand with the intravenous line was wrapped with a heating pad and warmed to 43°C to obtain “arterialized” venous blood (10). A blood sample was then withdrawn for blood lactate analysis. Maximal exercise testing to exhaustion was then performed with a previously described treadmill protocol (39). Maximal exercise performance was confirmed in the majority of subjects by analyzing for a plateau in \jo2 at peak exercise. This was defined as a change of
E. WOLFEL, WILLIAM R. HIATT, H. L. BRAMMELL, TRAVIS, AND LAWRENCE D. HORWITZ
Divisions of Cardiology and General Internal Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262 WOLFEL, EUGENE E., WILLIAM VICTORIA TRAVIS, AND LAWRENCE
R. HIATT, H. L. BRAMMELL, D. HORWITZ. Plasma catecholamine responses to exercise after training with ,8-adrenergic blockade. J. Appl. Physiol. 68(2): 586-593, 1990.-Exercise training has been shown to decrease plasma norepinephrine (NE) and epinephrine (EPI) levels during absolute levels of submaximal exercise, which may reflect alterations in sympathetic tone as a result of training. To determine if ,&adrenergic blockade altered these changes in the plasma concentration of catecholamines with exercise conditioning, we studied the effects of P-adrenergic blockade on NE and EPI at rest and during exercise in 24 healthy, male subjects after a 6-wk exercise training program. The subjects were randomized to placebo (P), atenolol 50 mg twice daily (A), and nadolol 40 mg twice daily (N). There were no changes in resting NE and EPI compared with pretraining values in any subject group. During the same absolute level of submaximal exercise NE decreased in P and A but was unchanged in N, whereas EPI decreased only in P. At maximal exercise all three groups developed significant increases in NE after training that paralleled increases in systolic blood pressure. EPI at maximal exercise increased after training with N but was unchanged with P or A. These training-induced changes in plasma catecholamine levels were masked or blunted when the A and N groups were studied while still on medication after training. Thus ,&adrenergic blockade has important effects on adaptations of the sympathetic nervous system to training, especially during submaximal exercise. exercise training;
,8-adrenergic
antagonist
NERVOUS system activity plays an imporrole in both the hemodynamic and metabolic changes that occur with exercise (2). Resting plasma catecholamine levels, particularly norepinephrine, have served as indicators of the degree of sympathetic activation in normal healthy individuals (4), hypertensive patients (l3), and patients with cardiac disease (14). Exercise training results in a reduction in sympathetic tone, and decreases in plasma norepinephrine levels during exercise have been reported in both healthy individuals and cardiac patients after training (3, 8, 27). Although plasma levels reflect both the release and uptake of catecholamines, they seem to parallel the changes in turnover seen with exercise training (20). Thus plasma catecholamines can serve as markers for changes in sympathetic activity that occur with training. ,6-Adrenergic blockade has been shown to alter both SYMPATHETIC
tant
586
0161-7567/90
$1.50 Copyright
the hemodynamic and metabolic changes that occur with exercise (11, 32). During acute exercise several studies have shown reductions in maximal O2 consumption . (9), and (VO 2 max) (35, 38), exercise hemodynamics plasma levels of free fatty acids, glucose, and lactate (22) with ,&adrenergic blockade. The metabolic effects have been shown to be more pronounced with blockade of p2adrenergic receptors (18, 24). Measurements of plasma catecholamines during exercise with both selective and nonselective ,&adrenergic blockade have shown variable results with either no change (31) or an increase at rest and during exercise (6) compared with placebo. The importance of sympathetic stimulation during exercise training is somewhat unclear. Animal experiments have shown training effects from chronic infusions of sympathetic agonists (21) and reductions in training effects after P-adrenergic blockade (17), suggesting that some level of sympathetic stimulation is necessary for exercise training to occur. Some studies of human subjects with ,6-adrenergic blockade during training have reported attenuation of training effects (23, 28, 39), whereas in others unaltered conditioning effects were noted (25, 30, 34, 37). We sought to characterize the interaction between the sympathetic nervous system and exercise conditioning by measuring plasma catecholamine levels in healthy, young men who underwent an intense training regimen, randomized among groups with intact sympathetic control (placebo), cardioselective P-adrenergic blockade (atenolol), and nonselective ,6-adrenergic blockade (nadolol). We hypothesized that ,6-adrenergic blockade would attenuate the responses to an aerobic training program through alterations in the sympathetic nervous system and that plasma catecholamine levels would reflect these alterations. METHODS
Study design. Twenty-four healthy, untrained men, aged 21-35 yr, participated in the study. Written consent was obtained from each subject, and the project was approved by the Human Subjects Committee of the University of Colorado Health Sciences Center. All subjects underwent an initial maximal treadmill test before entry into the study for familiarization with the treadmill protocol. The subjects then underwent a series of graded, maximal treadmill tests as previously described (39).
0 1990 the American
Physiological
Society
Downloaded from www.physiology.org/journal/jappl at Glasgow Univ Lib (130.209.006.061) on February 13, 2019.
PLASMA
CATECHOLAMINES
AND
Initial testing (test I) was performed before exercise training or drug dosing. Subjects were then stratified by Tjo2 maxinto matched trios and randomized into placebo, selective (atenolol), or nonselective (nadolol) ,&-adrenergic blockade groups. Nadolol was prescribed at a dose of 40 mg twice a day and atenolol as 50 mg twice a day. The investigators and technical staff directly involved in testing or exercise training were blinded as to treatment. The degree of ,&-adrenergic blockade was assessed by the reduction in heart rate at maximal exercise on a treadmill test performed 5 days after the initiation of drug therapy (test 11). ,&-Adrenergic blockade was determined by the change in calf vascular resistance during an epinephrine infusion before and after drug administration as previously described (19). The vascular response to epinephrine was quite different between atenolol and nadolol with a marked increase in vascular resistance with nadolol and vasodilation with atenolol. The subjects then underwent a 6-wk exercise program of heart rate-monitored circuit training consisting of 50 min of treadmill walking, stationary cycling, and step walking three times a week and a 40-min run twice a week. All subjects trained at >85% of their maximal heart rate attained during test 11, which corresponded to 80% of their entry Tjozmax on drug or placebo. The details of the training regimen and the monitoring of compliance are described in a prior report (39). At the end of the 6th wk of training, another treadmill test was performed while the subjects were still taking medication (test 111). All drugs were discontinued while the subjects continued to exercise for 2 more days. A final treadmill test was performed 4-6 days after discontinuation of all drugs (test IV). Tread&I protocol. Each subject fasted at least 4 h before testing. A 20-gauge catheter was inserted in a retrograde fashion into a vein draining the dorsum of the hand, after which the subject rested supine in a quiet room for 30 min. Heart rate and blood pressure were then recorded, and a blood sample was withdrawn for plasma catecholamine analysis. The hand with the intravenous line was wrapped with a heating pad and warmed to 43°C to obtain “arterialized” venous blood (10). A blood sample was then withdrawn for blood lactate analysis. Maximal exercise testing to exhaustion was then performed with a previously described treadmill protocol (39). Maximal exercise performance was confirmed in the majority of subjects by analyzing for a plateau in \jo2 at peak exercise. This was defined as a change of
