Both astronauts and highly trained endurance athletes seem to experience orthostatic intolerance to a greater extent than their earth-bound, nontrained counterparts (20). Although many cardiovascular adaptations to microgravity-induced deconditioning and terrestrial exercise training are opposite (3,6), both microgravity exposure and chronic endurance exercise training may decrease arterial baroreflex sensitivity (2,28). Compared with measurements made before flight, astronauts have returned from space with reduced carotid-cardiac baroreflex gain (11) and decreased ability to increase peripheral resistance (2) and plasma norepinephrine concentrations (9) during standing. Similarly, some highly trained endurance athletes have reduced baroreflex sensitivity (35) and reduced capacity to regulate arterial pressure during lower body suction (28). Although the etiology of orthostatic intolerance is multifactorial (20), it remains possible that both athletes and astronauts who are susceptible to orthostatic hypotension have blunted sympathetic responses to acute reductions of arterial pressure. Direct evidence for our speculation is presented in Figure 1, which shows the onset of syncope in a competitive cyclist during passive head-up tilt. To our knowledge, these data are the only in existence demonstrating reductions of directly-recorded muscle sympathetic nerve activity despite falling arterial pressures in an endurance athlete during an orthostatic challenge.
;)
FIGURE 1: The onset of presyncope (nausea, light-headedness, blurred vision) in a highly conditioned competitive cyclist (aerobic capacity was not measured); the arrow indicates the point where subject complained of symptoms; data from Cooke, et al. J. Physiol. 517:617–628, 1999. Figure previously unpublished.
Levine (20) has suggested that the propensity for orthostatic intolerance may be conceptualized by plotting a “U” shape, with astronauts or subjects undergoing head-down tilt bedrest at one end and highly conditioned endurance athletes at the other. With this construct, it seems likely that arterial baroreflex sensitivity is optimized with moderate, but not extensive endurance conditioning programs. Subjects who begin an exercise training program in an untrained state might improve their cardiovagal baroreflex sensitivity (34) and reduce their baseline muscle sympathetic nerve activity. Increased vagal and reduced sympathetic activity is opposite to the relation that seems to obtain in space (6,21), as well as in patients with hypertension (13) or heart failure (27). Athletes tend to have high vagal tone at rest (12), but it is not at all clear that short-term conditioning programs increase vagal responses to baroreceptor stimulation. In fact, exercise training has been shown to either increase (1), decrease (32) or not affect (29) cardiovagal baroreflex sensitivity.
Valsalva’s maneuver provokes reproducible changes of arterial pressure which both trigger and reflect autonomic responses, and is a time honored test of human arterial baroreflex function (7). Valsalva straining reduces venous return and induces predictable, reproducible arterial pressure changes that drive both sympathetic and cardiovagal baroreflex responses (33). Cox et al. (4) recently found that microgravity exposure decreases cardiovagal baroreflex gain and increases muscle sympathetic nerve responses to Valsalva’s maneuver. To gain insight into similarities and differences between cardiovascular responses to microgravity and terrestrial exercise, we designed an experiment similar to the experiment Cox et al. (4) conducted in space. We used Valsalva’s maneuver to evaluate vagal and sympathetic baroreflex responses of healthy young men before and after aerobic conditioning. We tested the hypothesis that exercise training would increase cardiovagal, and reduce sympathetic responses to acute changes of arterial pressure.
METHODS
Subjects
We studied 11 healthy men (22.3 ± 1.1 yr, 179.8 ± 8.9 cm, 88 ± 16.5 kg; mean age, height, weight ± SD). All subjects were nonsmokers, had no history of autonomic dysfunction, and passed a physical examination before entry into this study. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, and was approved by the Human Research Committee at Michigan Technological University, Houghton, MI., U.S. All subjects gave their written informed consent before participating.
Measurements
We recorded the electrocardiogram, continuous arterial pressure (Arterial Tonometry, Colin Medical Instruments, San Antonio, TX), respiratory rate (pneumatic bellows, Harvard Apparatus, Holliston, MA), and muscle sympathetic nerve activity (Nerve Traffic Analyzer, Model 662C-1, University of Iowa Bioengineering, Iowa City, IA). We sampled data at 500 Hz, and saved the data to computer with commercial hardware and software (WINDAQ, Dataq Instruments, Akron, OH).
To record efferent sympathetic nerve activity, we impaled a peroneal nerve at the popliteal fossa with a tungsten microelectrode (Frederick Haer and Co., Bowdoinham, ME). A reference electrode was inserted subcutaneously 2–3 cm from the recording electrode. Both electrodes were connected to a differential preamplifier, and then to an amplifier (total gain of 70,000) where the nerve signal was band-pass filtered (700–2000 Hz) and integrated (time constant, 0.1 s) to obtain mean voltage neurograms. Satisfactory recordings of muscle sympathetic nerve activity were defined by spontaneous, pulse-synchronous bursts that increased during end-expiratory apnea or Valsalva straining, and did not change during tactile or auditory stimulation.
Valsalva testing
Subjects arrived at the laboratory after having abstained from caffeine and exercise for at least 12 h. Subjects were instrumented for ECG, arterial pressure, and respiratory monitoring, and then microneurography was performed. Micro-electrode probing was limited to 1 h. Valsalva testing was conducted without direct recordings of sympathetic traffic if satisfactory nerve recordings could not be made within our self-imposed 1 h time limit.
All tests were performed with subjects in the supine position. We recorded baseline data while subjects breathed spontaneously for 5 min. We then recorded a second baseline period while subjects controlled their respiratory rates by breathing with a metronome at 15 breaths per min (0.25 Hz) for 5 min. We asked our subjects to strictly control their breathing for two reasons. First, respiration gates sympathetic nerve traffic such that bursts occur more often in expiration than inspiration. Large, deep breaths (as might occur during a sigh) could potentially confound baseline sympathetic traffic by prolonging the expiratory phase of breathing. Second, respiratory rate profoundly affects respiratory sinus arrhythmia. Although not a primary purpose of this investigation, including a period of controlled frequency breathing would allow us the opportunity to evaluate the effects of exercise training on baseline vagal-cardiac control. Controlled frequency breathing was followed by 3 Valsalva maneuvers. To perform a Valsalva maneuver, subjects exhaled forcefully through a mouthpiece and rubber tube (with a leak control valve) connected to an analog manometer. Subjects were instructed to exhale to 40 mm Hg pressure, and to hold that pressure until signaled to stop. Three 15-s Valsalva maneuvers were performed, separated by a 1 min recovery. Valsalva tests were performed before and after exercise training.
Exercise testing and training
To avoid potential confounding influences of prior exercise on autonomic function, all Valsalva tests were performed in the morning, and exercise tests were performed in the afternoon. For the exercise test, subjects were seated on a cycle ergometer (Monark, Varberg, Sweden), instrumented with a heart rate monitor (Polar Electro Oy, Kempele, Finland) and respiratory head-gear housing a mouthpiece and two-way breathing valve (Hans Rudolph, Kansas City, MO). A hose was connected from a dry gas meter (Harvard Apparatus, Holliston, MA) to the inspiratory side of the breathing valve, and a second hose was connected from the expiratory side of the breathing valve to a nondiffusible Douglas bag. The exercise testing protocol consisted of a 4-min warm up at 60 W, followed by incremental 4-min stages beginning at 120 W, increasing by 30 W, and continuing until volitional exhaustion. Inspired volumes were measured, and expired air was collected during the final min of each 4-min exercise stage. Ratings of perceived exertion were recorded at the beginning of the final min, and heart rates were recorded 15 s before the end of the final minute of each stage. Expired O2 and CO2 fractions were analyzed for each stage with bench-top analyzers (Vacu-Med, Ventura, CA). The volume of oxygen consumed during exercise (V̇O2) was calculated using standard equations, and converted to STPD (Standard Temperature and Pressure Dry). V̇O2 max was taken as the maximum volume of oxygen consumed during the final minute of the final exercise stage tolerated by the subject. V̇O2 and V̇O2 max were measured before and after exercise training.
Following the initial exercise and Valsalva tests, subjects returned to the laboratory for exercise training. All training sessions were monitored and recorded by laboratory assistants. The exercise training protocol consisted of a warm-up sufficient to raise subjects’ heart rates to 70% of their maximum heart rate (derived from the maximal aerobic capacity test), followed by 30 min of exercise at ≥ 70% maximum heart rate. Heart rate was recorded every 5 min, and flywheel resistance and/or pedaling frequency was adjusted to maintain exercise intensity throughout the sessions. Subjects performed the exercise training protocol 3 d · wk−1 for 4 wk.
Data analysis
All data were imported into a customized software program for analysis [Cardio-Pulmonary Research Software for Windows, (WinCPRS), Absolute Aliens Ay, Turku, Finland]. R-waves and systolic and diastolic pressures were detected from continuous waveforms and marked at their occurrences in time. Stroke volume and cardiac output were estimated using the pulse contour method (15) adapted for WinCPRS.
Vagal baroreflex gain
For each subject, we identified the four Valsalva phases as recently outlined by Smith et al. (33). We evaluated sympathetic nerve responses to phase II diastolic pressure reductions, and R-R interval responses to phase IV systolic pressure elevations. Phase II began at the highest systolic pressure value recorded at the onset of strain, and ended with abrupt pressure reductions at the end of the 15 s strain period. Phase IV began with the first systolic pressure value above the last value recorded during phase II and immediately after pressure drops during phase III. We identified the end of phase IV as the first data point where systolic pressure began to decline after systolic pressure overshoot (33). Figure 2 shows a representative response to Valsalva straining in one subject, with phases identified.
FIGURE 2: Representative response to Valsalva straining in one subject; Valsalva phases are marked in the arterial pressure window; region of inclusion for sympathetic bursts occurring during phase II is shown with vertical dotted lines in the neurogram window; region of cardiovagal baroreflex gain calculation during phase IV is shown with vertical dotted lines in the systolic pressure and R-R interval windows.
We used the slope method of Kautzner, et al. (17) to assess cardiovagal baroreflex sensitivity during phase IV arterial pressure elevations. We calculated the magnitude of increases in R-R intervals as functions of increases in systolic pressures with linear regression analysis. We used a minimum of 3 consecutively-increasing systolic pressure values and corresponding changes in R-R intervals – advanced by one beat (17). To be considered a valid sequence, correlation coefficients were ≥ 0.90.
Muscle sympathetic nerve activity
Bursts of muscle sympathetic nerve traffic were automatically detected from several criteria. Potential bursts were identified within a 0.5 s search window centered on an expected burst peak latency from preceding R-waves of 1.3 s. Potential bursts were also evaluated based on amplitude, using a signal-to-noise baseline criteria of about 3:1. Mean burst peak latencies were calculated from the first iteration of the burst detection algorithm; these mean latencies were then used as criteria for identifying bursts for a second iteration. This procedure was used until further latency corrections failed to detect additional bursts or change average burst latency. The amplitude, or area of individual sympathetic bursts, depends largely on electrode position. Because of this, it is impossible to compare changes in burst size between subjects, or in the same subject twice unless bursts are first normalized to some reference value. Therefore, the integral of all sympathetic bursts occurring during the 5 min baseline period was divided by the number of bursts to derive an average control burst area. The area of each sympathetic burst recorded subsequently was divided by this number to derive normalized burst areas that could be compared to baseline values. Using this technique, bursts that are identical in size to average control bursts are assigned a value of 1.0.
We expressed muscle sympathetic nerve activity as bursts·min−1, average normalized burst areas, and total sympathetic activity (the product of bursts · min−1 and normalized burst areas) during spontaneous and controlled frequency breathing. We integrated all sympathetic bursts occurring during the 15 s period of Valsalva straining to derive normalized areas. Within this 15 s period, we again calculated total sympathetic activity. To determine sympathetic activation during Valsalva straining, we divided total muscle sympathetic nerve activity by the maximum diastolic pressure decreases during phase II.
Statistical analysis
All statistical tests were run with commercial software (SAS Institute, Cary, NC). Statistical comparisons among each variable of interest were performed with analysis of variance (ANOVA) with repeated measurements on time (pre- vs postexercise training). Dependent variables were compared using a single mean derived during baseline and controlled frequency breathing protocols. Dependent variables were compared using means derived from three Valsalva trials during Valsalva maneuvers. The reproducibility of Valsalva straining was evaluated by calculating coefficients of variation. We considered differences significant when P < 0.05.
RESULTS
All subjects completed the exercise training program. Ten subjects completed 100% of all training sessions as scheduled (3 d · week−1). One subject missed two sessions, but completed these sessions by extending the program for one week. Nine out of 11 nerve recordings were successful before exercise training, but of these, two were unsuccessful after exercise training. Because of this, we report pre- and postexercise nerve data for 7 of our 11 subjects. All data are expressed as means ± SE unless otherwise specified.
Exercise
Average heart rates (expressed as a percentage of maximal heart rate) during exercise training sessions were: 70% ± 0.4 for week 1; 73% ± 0.8 for week 2; 77% ± 1.1 for week 3; and 81% ± 1.2 for week 4. Figure 3 shows that exercising at these intensities 3 d · wk−1 for 4 wk significantly decreased submaximal exercising heart rates (P = 0.01) and increased aerobic capacity (P = 0.04). Heart rate at V̇O2 max did not change with exercise training (P = 0.45).
FIGURE 3: Submaximal and maximal heart rate responses to V̇O2max testing (A), and V̇O2max changes (B) before (filled symbols) and after (open symbols) exercise training (N = 11); lines connect individual subjects; square symbols are means ± SE; L·min−1, L per min; bpm, beats per min; asterisk (*) = significantly different from corresponding pretraining values.
Spontaneous and controlled frequency breathing
We found that respiratory rates during spontaneous breathing were not significantly different from respiratory rates during controlled frequency breathing (Table 1), but were more variable. Average respiratory rates ranged from 8.8 to 21.6 breaths · min−1 during spontaneous breathing, and ranged only from 14.8 to 15.4 breaths · min−1 during controlled frequency breathing. Variables recorded during baseline rest and controlled frequency breathing before and after exercise training are shown in Table 1. Exercise training significantly increased R-R interval standard deviations (P = 0.03), but did not change average R-R intervals. Exercise training did not affect resting arterial pressure, cardiac output, stroke volume, or muscle sympathetic nerve activity (P > 0.05).
Table 1: Cardiovascular variables recorded during baseline supine rest and controlled frequency breathing before and after exercise training.
Valsalva Maneuvers
Table 2 shows that exercise training did not affect the magnitude of change in arterial pressures or R-R intervals during Valsalva maneuvers. Average beat-by-beat arterial pressure changes during Valsalva straining are shown for all subjects in Figure 4. Table 2 also shows that exercise training decreased average normalized muscle sympathetic burst areas during phase II straining (P = 0.03), but did not affect total sympathetic nerve activity (P = 0.31).
Table 2: Cardiovascular responses to Valsalva straining before and after exercise training.
FIGURE 4: Average beat-by-beat changes in arterial pressure during Valsalva straining before and after exercise training (N = 11).
We derived a ‘sympathetic index’ to relate sympathetic activation to decreases in diastolic pressure by dividing total muscle sympathetic nerve traffic by the difference between maximum and minimum diastolic pressures during phase II straining. The sympathetic index was not affected by exercise training (1.49 ± 0.49 before exercise training, and 1.10 ± 0.19 units · Δ diastolic pressure−1 after exercise training;P = 0.12).
Exercise training significantly increased cardiovagal baroreflex sensitivity during phase IV Valsalva straining from 15.0 ± 1.0 before training, to 25.0 ± 4.0 ms · mm Hg−1 after training (P = 0.03). However, a high degree of variability among subjects resulted in high coefficients of variation [Others have reported coefficients of variation for Valsalva maneuvers of approximately 29% (22)]. The mean coefficients of variation for the phase IV systolic pressure-to-R-R interval responses between the three trials before and after exercise training were 21 and 26% (range from 5 to 45%). Despite the wide range of responses, every subject increased their cardiovagal baroreflex sensitivity after exercise training. Changes of sympathetic and vagal responses to Valsalva straining with exercise training are shown in Figure 5.
FIGURE 5: Sympathetic (A) and vagal (B) responses to Valsalva straining before and after exercise training; sympathetic index depicts the quotient of total muscle sympathetic nerve activity and diastolic pressure reductions during phase II straining (N = 7); cardiovagal baroreflex sensitivity depicts R-R interval responses to systolic pressure elevations during phase IV (N = 11); asterisk (*) = significantly different from corresponding pretraining values.
DISCUSSION
We studied autonomic cardiovascular control mechanisms before and after 4 wk of strictly-controlled aerobic conditioning in a group of healthy young men. Our principal new finding is that exercise training affects vagal and sympathetic mechanisms differently. Aerobic conditioning does not change baseline sympathetic activity or the magnitude of muscle sympathetic nerve activation during phase II reductions of diastolic pressure. Exercise training dramatically increases R-R interval prolongations to phase IV systolic pressure elevations. We conclude that short-duration aerobic exercise training increases vagal, but does not affect sympathetic responses to Valsalva’s maneuver.
Aerobic capacity
We closely monitored our research subjects during each training session to ensure that adequate exercise intensities were reached and maintained (≥70% max heart rate). Increases of aerobic capacity occur quickly when research subjects are untrained, and we found that our training program significantly increased aerobic capacity in our subjects by about 7% (Figure 3B). Although our estimated values for supine resting cardiac output and stroke volume did not change (Table 1), exercise training caused a significant decrease in submaximal heart rates during exercise testing (Figure 3A). Our observations show that 4 wk of moderate aerobic conditioning is sufficient to induce functional cardiovascular adaptations in previously sedentary healthy young men.
Cardiovagal responses
At normal respiratory frequencies, variations in beat-to-beat heart period (R-R interval) are proportional to, and predominantly controlled by vagus nerve activity. Thus, some have suggested that analysis of R-R intervals and R-R interval oscillations at or around the respiratory frequency directly reflects vagal-cardiac control (16). Although not a primary purpose of this investigation, we estimated vagal-cardiac control by analyzing R-R intervals and R-R interval standard deviations during controlled frequency breathing before and after exercise training. Unfortunately, our results are inconsistent. Exercise training did not affect resting R-R intervals, but did increase R-R interval standard deviations (Table 1). Of note, R-R intervals tended to increase, but these increases did not reach statistical significance (P = 0.17). Although increases of R-R interval standard deviations during controlled frequency breathing suggest an increase in vagal-cardiac tone, we can offer no explanation why baseline R-R intervals did not similarly increase. It is possible that our training program was not of sufficient duration to induce baseline changes of vagal-cardiac control. For example, Shi, et al. (31) showed clear increases of vagal tone after an extensive 8 mo endurance training program. Although others have found that 4 wk of aerobic conditioning is sufficient to increase vagal-cardiac tone (19), similar conclusions based on data from the present study are not well supported. Future studies would benefit from extending the endurance training duration beyond 4 wk.
Exposure to microgravity decreases cardiac vagal tone, carotid-cardiac baroreflex sensitivity (6), and vagal responses to Valsalva’s maneuver (4). Cardiovascular deconditioning of astronauts, including resetting of cardiovagal baroreceptor responsiveness, is likely mediated by chronic blood volume reductions and relative inactivity (6). It therefore seems reasonable to suspect that exercise training, which transiently resets arterial baroreflexes to exercise pressures (25), and acutely and chronically increases blood volumes (3), would induce effects opposite to those seen in astronauts. Others have documented a positive relationship between exercise training and cardiovagal baroreflex sensitivity in exercising hypertensives (34) and middle-aged adults (24). Monahan et al. (24) showed that cardiovagal baroreflex sensitivity is increased even after exercise training programs that do not increase aerobic capacity significantly. Four weeks of aerobic exercise was sufficient to significantly increase vagal baroreflex sensitivity in patients after myocardial infarction (19). Because enhanced vagal-cardiac tone is predictive of future cardiovascular health (18), our results suggest that a 4 wk program of aerobic conditioning is sufficient to induce healthy autonomic adaptations in young men.
Sympathetic responses
There is an abundant literature describing the effects of exercise training on vagal-cardiac control, but the effects on sympathetic activity are not well defined. Exercise training either decreases (14) or does not affect (30) resting muscle sympathetic nerve traffic. We had anticipated a reduction of baseline muscle sympathetic nerve activity because exercise training seems to reduce baseline plasma norepinephrine levels (5), and plasma norepinephrine levels correlate closely with directly-recorded muscle sympathetic nerve activity (27). In addition, hypertension is associated with elevated baseline sympathetic activity (13), and exercise training causes parallel reductions of arterial pressure and sympathetic tone (26). However, our results show that 4 wk of strictly-controlled aerobic cycle exercise training is not sufficient to significantly alter baseline muscle sympathetic nerve activity in previously untrained, healthy young men (Table 1).
Muscle sympathetic nerve activity increased appropriately to decreases in diastolic pressure during phase II reductions, and total muscle sympathetic nerve activity was not affected by exercise training. However, we did detect that normalized areas of sympathetic bursts during Valsalva straining were significantly less after aerobic conditioning (Table 2). It is not clear that reductions in the size of sympathetic bursts are physiologically significant. However, it is possible that decreased normalized burst areas indicate changes in neuronal recruitment patterns within a sympathetic burst. Macefield et al. (23) evaluated characteristics of individual vasoconstrictor neuronal firings (as opposed to multi-unit firings recorded in the present study), and found that individual motoneurons fire once per sympathetic burst, that these firings occur in response to decreases in arterial pressure, and that these firings seem to occur in a fixed order within a burst. They proposed that the order of individual vasoconstrictor motoneuron firings within a sympathetic burst may optimize the buffering capacity of the sympathetic nervous system to arterial pressure reductions (23). In the present study, exercise training did not affect the magnitude of arterial pressure reductions during phase II Valsalva straining, but it did decrease the size of sympathetic bursts occurring as a consequence. Therefore, we suggest that exercise training may decrease the number of individual vasoconstrictor neurons firing per sympathetic burst or alter the normally-ordered recruitment of neuronal firings. Such an adaptation may eventually decrease sympathetic responsiveness to acute blood pressure reductions (as suggested by Figure 1), but this speculation can only be evaluated by directly comparing the effects of exercise on individual vasoconstrictor motoneuron firings.
Our speculation that exercise training would decrease sympathetic responses to diastolic pressure reductions derive partly from recent studies on astronauts. Ertl et al. (8) found that resting muscle sympathetic nerve activity is increased in microgravity, and Cox et al. (4) found that microgravity increases sympathetic responses to Valsalva straining. However, Cox et al. (4) also found that diastolic pressure changes in space are greater during phase II Valsalva straining compared to changes on Earth, and therefore concluded that sympathetic activity in space seems to increase appropriately to the magnitude of the arterial pressure stimulus. With this interpretation, increases of muscle sympathetic nerve activity with microgravity relate directly to hypovolemia and the resulting increased arterial pressure response to Valsalva straining. Although we did not measure blood volume in the present study, Fritsch-Yelle, et al. (10) showed that arterial pressure responses to Valsalva’s maneuver are altered profoundly by increases or decreases in blood volume. Changes in blood volumes likely did not impact our results importantly because arterial pressure responses to Valsalva straining were not affected by exercise training. We therefore conclude that short-duration exercise training programs preserve (or have no effect on) sympathetic baroreflex responses.
SUMMARY
We evaluated vagal and sympathetic responses to Valsalva maneuvers in previously sedentary young men before and after 4 wk of aerobic cycle conditioning. Based partly on evidence from Earth and partly on evidence from space, we speculated that autonomic cardiovascular adaptations to exercise and microgravity are opposite. As expected, we found that exercise training increases cardiovagal baroreceptor sensitivity during arterial pressure elevations. Such adaptations are predictive of future cardiovascular health. Contrary to our expectations, exercise training did not affect sympathetic activation during arterial pressure reductions. Although some athletes may suffer episodes of orthostatic intolerance due to inappropriate sympathetic responses to arterial pressure decreases, sympathetic responsiveness does not seem to be affected by short-term conditioning programs.
We thank Dr. Douglas McKenzie of Portage Hospital, Hancock, Michigan, for conducting physical examinations of our research volunteers. We also thank Mr. Kelly Hrabinsky and the staff of Portage Rehabilitation, Houghton, Michigan, for assisting us in this project. This study was supported by a Scientist Development Grant from the American Heart Association (0030203N).
Address for correspondence: William H. Cooke, The Department of Biomedical Engineering, Michigan Technological University, 1400 Townsend Dr., Houghton, MI. 49931; E-mail: [email protected]
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