Short-duration spaceflight impairs human carotid baroreceptor-cardiac reflex responses JANICE M. FRITSCH, MICHELE M. JONES,
JOHN B. CHARLES, BARBARA AND DWAIN L. ECKBERG
S. BENNETT,
Departments of Medicine and Physiology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center and Medical College of Virginia, Richmond, Virginia 23249; Space Biomedical Research Institute, National Aeronautics and Space Administration Johnson Space Center, and KRUG Life Sciences, Hous ton, Texas 77058 FRITSCH,JANICE M., JOHN B. CHARLES,BARBARA S.BENNETT, MICHELE M. JONES, AND DWAIN L. ECKBERG. Shortduration spaceflight impairs human carotid baroreceptor-cardiac reflex responses. J. Appl. Physiol. 73(2): 664-671,1992.-Orthostatic intolerance is a predictable but poorly understood consequence of space travel. Because arterial baroreceptors modulate abrupt pressure transients, we tested the hypothesis that spaceflight impairs baroreflex mechanisms. We studied vagally mediated carotid baroreceptor-cardiac reflex responses (provoked by neck pressure changes) in the supine position and heart rate and blood pressure in the supine and standing positions in 16 astronauts before and after 4- to s-day Space Shuttle missions. On landing day, resting R-R intervals and standard deviations, and the slope, range, and position of operational points on the carotid transmural pressure-sinus node response relation were all reduced relative to preflight. Stand tests on landing day revealed two separate groups (one maintained standing arterial pressure better) that were separated by preflight slopes, operational points, and supine and standing R-R intervals and by preflight-to-postflight changes in standing pressures, body weights, and operational points. Our results suggest that short-duration spaceflight leads to significant reductions in vagal control of the sinus node that may contribute to, but do not account completely for, orthostatic intolerance. microgravity;
orthostatic;
vagal
EXPOSURETOWEIGHTLESSNESS alterspostflightcardiovascular responses to exercise and standing. Although these changes are probably initiated during flight, they are not known to impair cardiovascular performance in space (7). However, functional problems become apparent on landing, when most astronauts have reduced exercise capacity and orthostatic tolerance (5). The cause of orthostatic intolerance is unclear. Loss of plasma volume during weightlessness (16) may be partly responsible. However, acute comparable blood volume reductions usually do not provoke orthostatic hypotension (32), and repletion of blood volume after simulated weightlessness does not completely prevent orthostatic hypotension (3). This study explores a possibility, suggested by groundbased research, that impairment of normal baroreflex mechanisms contributes to postweightlessness orthostatic intolerance. Head-down tilt [a widely used simulation of weightlessness (18)] reduces R-R interval responses to carotid baroreceptor stimulation (6, 11); in
one study (6), such reductions were correlated directly with the magnitude of post-bed-rest blood pressure reductions during standing. We studied vagally mediated baroreceptor-cardiac reflex responses of American astronauts before and after Space Shuttle missions lasting 4-5 days and correlated baroreflex responses with blood pressure and heart rate responses to standing. Our results suggest that spaceflight reduces baseline levels of vagal-cardiac outflow and vagally mediated responses to changes of arterial baroreceptor input. Furthermore, our data suggest that these changes contribute to postflight reductions of astronauts’ ability to maintain standing arterial pressures. MATERIALS
AND METHODS
Subjects and protocol. We studied 16 astronauts (15 males and 1 female), whose average age was 43 t 4 (SE) yr (range 36-54 yr), before and after Space Shuttle missions lasting 4-5 days. Our protocol was approved by the Johnson Space Center Human Research Policies and Procedures Committee and the Human Research Committees of the Hunter Holmes McGuire Department of Veterans Affairs Medical Center and the Medical College of Virginia. Preflight studies were performed nominally 10 and 5 days before launch; in practice, preflight data were collected between 13 and 7 days and again between 7 and 5 days before launch. Acceptable postflight data were collected on landing day (n = ll), on the 2nd and 3rd days after landing (n = 16), and on postflight days 8, 9, or 10 (n = 12). The electrocardiogram, respiration (abdominal bellows connected to a strain gauge pressure transducer), and neck chamber pressure were recorded by FM tape and strip chart recorders. The electrocardiogram and respiration were recorded during the last 5 min of a 20-min rest period before any intervention. Resting vagal-cardisc activity was estimated from average R-R intervals and their standard deviations (9,20). Blood pressure was measured manually with a sphygmomanometer before baroreceptor testing. Several aspects of this experiment were beyond our control. Eight crew members shifted their sleep-wake cycles in preparation for flight and took sleeping medications (flurazepam HCl, Roche; or temazepam, Sandoz)
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VAGAL
pressure, ~~;g
BAROREFLEXES
AND
665
SPACEFLIGHT
4i[l%% -65
R-R interval, msec
1400 1000 [ +
-
electrocardiogram FIG. 1. Original record showing neck sequence and responses of 1 subject (A) of that subject’s average responses to 7 sequences (B). Closed circle, operational
0-O 0
\
/
0 \
slope = 7.4 msec/mmHg
I I I I I 1.
P 0
0
carotid
50
0 I
/
pressure minimum
I I
I
I
100
150
distendina
T I I 1
01 range = 339 msec
I
minimum R-R
pressure and plot stimulus point.
J
at R-R I
200
w-essure, I
the night before the second preflight measurement (-5 days before launch); three crew members took temazepam within 24 h before landing. Data obtained on days after these medications were taken were discarded. For all other subjects, measurements made nominally 10 and 5 days before launch were averaged to obtain control values. We were unable to collect data on two subjects on landing day because of equipment malfunction. Baroreflex stimuli. After the rest period, a tightly sealing Silastic chamber was strapped to the anterior neck (35). A computer-controlled stepping motor-driven bellows delivered a fixed sequence of pressure and suction steps to the chamber during held expiration, as follows. Pressure was increased to ~40 mmHg for ~5 s, reduced by -15-mmHg decrements after each of the next seven R waves to about -65 mmHg, and finally returned to ambient levels. Responses from seven successful repetitions of this stimulus sequence during each experimental session were averaged. R-R intervals were plotted against carotid distending pressures (taken to be systolic minus neck chamber pressures). Figure 1 is an original record showing a neck pressure sequence and response of one subject and a plot of that subject’s average response to seven stimulus sequences. Earlier studies showed that these stimuli and baroreflex responses are highly reproducible (10, 19).
250
mmHg Prior studies (12,19) also showed that when data from such baroreflex stimuli are fitted to a four-parameter logistic equation, confidence limits are so large that derived equations do not describe the data accurately. Therefore, in this study baroreflex response relations were reduced to other parameters for analysis, including minimum, maximum, and range of R-R interval responses, carotid distending pressures at minimum and maximum R-R intervals, maximum slopes, and operational points. Maximum slopes were identified with linear regression analyses applied to each set of three consecutive pairs of data on the stimulus-response relation. Operational points were defined as [(R-R intervals at 0 mmHg neck pressure - minimum R-R intervals)/R-R interval range] X 100%. The operational point is a measure of the relative baroreflex buffering capacity for pressures above and below resting levels. (Thus when operational points are low, there is less relative buffering capacity for the hypotensive part of the stimulus, and when operational points are high, there is less relative buffering capacity for the hypertensive part of the stimulus.) The operational point has constraints because of the nature of the stimulus profile. This profile, the limits of which are defined by subject tolerance, fails to define a plateau at the minimum R-R interval in -20% of subjects. A true threshold cannot be defined in these sub-
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666
VAGAL
BAROREFLEXES
jects, and the operational point as calculated is not the true operational point of a classic sigmoid curve. We use it only to define the relative capacity to buffer the hypotensive portion of the stimulus profile we deliver. If that same stimulus is delivered before and after interventions, the operational point provides useful information. Stand test. Stand tests were performed on all subjects 10 days before launch, on landing day, and 3 days after landing. Blood pressure, measured manually with a sphygmomanometer, and heart rates were measured every minute for 10 consecutive min (5 during supine rest, 1 immediately after standing, and 4 during standing with subjects leaning against a wall with their heels 6 in. from the wall). The five supine blood pressures and heart rates were averaged to derive supine measurements. The maximum standing heart rate and its corresponding blood pressure were taken as the standing measurement. We used R-R intervals in these analyses because the relation between changes of R-R intervals and those of vagal-cardiac traffic is linear (21). The relation between heart rate and vagal-cardiac traffic is curvilinear; this makes comparisons before and after interventions difficult if baseline heart rate has changed. Fluid loading. All 16 subjects followed some fluid loading protocol before reentry. Most took salt tablets or salty food and 21 liter of water or juice. Many consumed 21 liter of fluid. All crew members had access to unlimited fluids between the time they exited the orbiter and entered the clinic where the studies were performed (12 h after landing). Statistics. All data are means t SE. Because some measured variables were not distributed normally (29), nonparametric statistical tests were used. We used the Wilcoxon signed-rank test (33) to identify differences among results obtained during experimental sessions and the Spearman test (13) to identify correlations among measurements. We applied cluster analysis (2) to identify groups according to blood pressure responses on landing day. Forward selection, backward elimination, and stepwise regression modeling methods (8) were used to predict changes of standing minus supine systolic pressure on landing day. The following factors were entered into the model as independent variables: maximum baroreflex slope and R-R interval range, operational point, and body weight. The entry level significance for these independent variables was set at P = 0.25. Results from forward selection and backward elimination methods were similar, and therefore only results from backward elimination analyses are presented. P < 0.05 was considered significant. RESULTS
Preflight reproducibility. Baroreflex responses measured 10 and 5 days before flight were not different. The range of R-R interval responses averaged 237 t 52 and 250 t 36 ms (P = 0.82), respectively, and the maximum slope averaged 5.0 t 0.8 and 5.0 t 0.7 ms/mmHg (P = 0.59). Because the two preflight measurements were so reproducible, they were averaged to derive preflight values. Control measurements. Average baseline measure-
AND
SPACEFLIGHT
ments for all subjects are given in Table 1. Baseline arterial pressure did not change throughout the study. Resting R-R intervals, their standard deviations, and body weight were all significantly reduced, but on landing day only. Baroreflex responses. Average R-R interval responses to carotid baroreceptor stimuli for all subjects are presented in Table 1, and responses measured on landing and subsequent days are shown in Figs. 2-4. Average slopes and ranges were reduced insignificantly on landing day and significantly on postflight days Z-10. On landing day (Fig. 2), the response relation was lower on the R-R interval axis (as reflected by minimum and maximum R-R intervals) but at the same position on the pressure axis (as reflected by carotid distending pressures at minimum and maximum R-R intervals). Also on landing day, maximum slopes and ranges were reduced in about one-half of the subjects, and the position of the operational point was reduced in 86% of them. By the 2nd day after landing (Table 1, Fig. 3), the average baroreflex slope and range were significantly reduced, but the operational point had returned to the preflight level. Compared with preflight levels, 60% of subjects had reduced slopes, 75% had reduced ranges, and 69% had lower operational points. By this time the average minimum, but not maximum, R-R intervals had returned toward a higher point on the R-R interval axis. The position of the response relation on the pressure axis still was not different from preflight. On the 3rd day after landing and thereafter (Table 1, Fig. 4), the average R-R interval slope and range remained significantly reduced. The average maximum RR interval was reduced on days 8-10. All other parameters were comparable to preflight values. Stand tests. Changes of systolic and diastolic pressures and heart rates on standing for all subjects are shown in Fig. 5. Preflight increases of systolic and diastolic pressures with standing were 11 ? 3 (107 t 3 to 118 t 1) and 15 + 3 (68 + 2 to 83 + 1) mmHg. The preflight maximum increase ofheart rate with standing was 16 t 1 (55 t 2 to 71 -+ 1) beats/min. On landing day, average increases of systolic and diastolic pressure were 5 t 3 (115 t 3 to 120 t 3, P = 0.04 f rom preflight) and 12 t 2 (76 t 3 to 88 t 2, P = 0.13) mmHg. Heart rate increases from supine to standing positions averaged 31 t 3 (65 t 7 to 96 t 4, P = 0.0008, from preflight) beats/min on landing day and were significantly larger than preflight values. Heart rate responses also were converted to R-R intervals for analysis. Decreases of R-R intervals with standing averaged 254 t 32 ms (1,113 t 35 to 859 t 30) before launch and 293 t 29 ms (933 t 29 to 640 t 28) on landing day (P = 0.052 from preflight). Correlations
between
stand
tests and baroreflex
data.
Systolic pressure responses to standing varied among subjects on landing day. Cluster analysis of these changes identified two groups of astronauts (r = 0.68, P < 0.01). Figure 6 illustrates the results of this analysis. One group maintained standing systolic pressures well, and the other did not. Responses of these two groups to standing are shown in Fig. 7. Comparisons between the two groups are shown in Table 2. In subjects who main-
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VAGAL TABLE
BAROREFLEXES
667
AND SPACEFLIGHT
1. Measurements from all subjects on all test days Postflight Preflight
Systolic pressure, mmHg Diastolic pressure, mmHg R-R interval, ms Standard deviation of R-R, ms Body weight, kg
Landing
2
3
8-10
116+2 75+1 1,123&42
116+2 73t2 965+25*
117t2 72k2 1,069+38
116t2 73k2 1,134-t39
116k2 74k2 1,069+31
62t6 75.6k4.0
40t4* 74.4t2.4*
58t6 75.2k2.4
55k5 75.3t2.4
47+5 75.4k2.1
3.6t0.6* 39.8k3.6
3.9t0.6* 52.4k4.7
3.9+0.6* 42.4k6.0
177+20* 1,213&41*
192+102* 1,084+35 1,275*43
189&27* 1,037+31 1,226*38*
92k9 160t6
82k7 157+7
75k2 161k5
Baroreflex
Maximum slope, ms/mmHg Operational point, % R-R interval, ms Range Minimum Maximum Carotid distending pressure, mmHg At minimum R-R At maximum R-R
Day
Day
measurements
5.Okl.O 48.9k3.5 243k47 1,081+43 1,324-+68
3.4t0.5 29.4+4.2-f 182k25 923k30” 1,104*31*
8Ok4 153t-8
1,036+39
83k4 172t4
Values are means + SE. All comparisons between landing day and preflight measurements used only 11 subjects; those between landing day and measurements taken 8-10 days after landing used only 12 subjects. * P < 0.05; t P -c 0.01. 1450
1450< E
0
y350
preflight
1250
T/ A
k-AHTA
T
-A
T
Al/A CY I (y
N
950
T/
3 .r
.,6-h T/ 0
landing day n=
oc I
11
rY
Tf T,A TA A’ 0-y 1
1050
carotid
100
distending
150
200
pressure,
mmHg
FIG. 2. Carotid baroreceptor vagal-cardiac reflex responses before flight and on landing day. Closed symbols, position of operational points. Average operational point was reduced significantly on landing day, but slope and range were not.
tained systolic pressure well, the average increase of systolic pressure with standing was 3 t 2 mmHg greater on landing day than before flight (systolic pressure increased from 110 to 121 mmHg before flight and from 110to 124 on landing day). In the other group of subjects, systolic pressure actually fell with standing on landing day so that it was actually 17 t 3 mmHg less on landing day than before flight. This difference between groups was significant (P = 0.0001). The two groups also differed significantly in preflight-to-postflight standing minus supine increases of diastolic pressure (0.9 t 3.9 vs. -9.3 t 4.6 mmHg, P = 0.031), preflight to postflight reductions of their operational points (-13.4 t 3.0 vs. -26.7 t 4.7%, P = 0.0005), and weight lost during the flight (-0.44 t 1.3 vs. -1.44 t 0.5 kg, P = 0.0001). Results from backward elimination analysis showed that preflight-to-postflight changes of standing minus supine systolic pressures on landing day were predicted primarily by preflight-to-postflight changes of operational point (P = 0.0041) and of body weight (P = 0.034). The R value for the model was 0.64 (P = 0.0034). No
/c:
MO 1
@
100 1
50
carotid
distending
.0-y-o *
-A
1
l
950 850
50
A-A.
A-
Y
i 850)
1
TTkT
z1150
I
n=16
-1250
A T,o
1
1
preflight sloDe=5.0 4 m&c/mmHg
E
rf
T/
1
landing + 2 slope=3.6 msec/mmHg I
I
150
200
pressure,
mmHg
FIG. 3. Carotid baroreceptor vagal-cardiac reflex responses before flight and 2 days after landing. Average slope and range were significantly reduced, but operational point (closed symbols) was not.
other variables (preflight or postflight) contributed to the model. The differences between the two groups extended to some preflight measurements. These differences are described in Table 2. Before flight the less resistant group had greater supine and standing R-R intervals and slower standing heart rates. Resting heart rates were also slower, although not significantly. In addition, the less resistant group had significantly larger slopes of the baroreflex response and significantly higher operational points. On landing day, baseline, minimum, and maximum RR intervals correlated directly with heart rate responses to standing (P = 0.003, 0.050, and 0.005, respectively). Slopes and ranges did not correlate with any variable measured during the stand test. By the 3rd day after landing, stand test responses were not different from preflight values. Heart rate increases with standing averaged 18 t 2 (55 t 2 to 73 t 3, P = 0.014) beats/min, and systolic and diastolic increases with standing averaged 5 t 2 (112 t 2 to 117 t 2, P = 0.78) and 12 t 2 (69 t 2 to 81 t 1, P = 0.95) mmHg. The
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668
VAGAL
BAROREFLEXES
AND
SPACEFLIGHT
n = 14 r = 0.68 p ( 0.01
0
H E
u-
-60
0
250
I 10I
I
1
I
,
preflight 4. Average *P < 0.05.
slopes,
landing ranges,
0 *
1
2
1
4
,
6(8-10)
post-flight
and operational
days points
throughout
average R-R interval was reduced 287 t 25 (1,131 t 50 to 844 t 38) ms on standing on this day. The group differences noted on landing day were no longer evident. DISCUSSION
We delivered a profile of neck pressure and suction changes to 16 American astronauts before and after brief (4 to s-day) Space Shuttle missions to test the hypothesis that space travel impairs human carotid baroreceptor-cardiac reflex responses. This study documents sig40 m El
n=
= preflight = landing
.-t
day
E 30% 4 ii n
16
20 2 F 1oY iii L systolic
change, FIG.
supine ference
diastolic
standing
heart
minus
rate
Oa
supine
5. Preflight and postflight differences between standing systolic and diastolic pressures and heart rate. Significant between groups: *P < 0.05; **P < 0.01.
0
change
point,
I
20 in
%
FIG. 6. Preflight-to-postflight (landing day) changes of operational points and systolic pressure responses to standing. Linear regression correlation coefficients are for all data. Cluster analysis (see MATERIALS AND METHODS) of these data identified 2 distinct groups, which we have termed less and more resistant to postural change. Hatched area, more resistant group.
1-
0 -o’*
-20
to postflight
operational
1
FIG.
-40
pre-
\
study.
“‘-40--
and dif-
n&ant postflight reductions of estimated baseline vagal-cardiac traffic and operational points on landing day and persistent reductions in slope and range of the carotid baroreceptor-cardiac reflex response. Cluster analysis suggested that the astronauts could be divided into two groups according to how well they maintained standing systolic pressure on landing day. These groups were also significantly different in other respects. Astronauts who supported their systolic pressures poorly on landing day had slower heart rates and greater gain of vagally mediated baroreflex responses preflight and greater weight loss and reductions of baroreflex operational points postflight than astronauts who supported pressures well. Vagal responseson landing day. Several measurements point toward reductions of baseline vagal-cardiac traffic and vagally mediated responses to changes of baroreceptor input on landing day. Average baseline R-R interval and standard deviations were less. Average baseline heart rate was significantly greater, and average baroreflex gain and R-R interval range were insignificantly less than preflight. Lack of statistical significance of baroreflex slope and range reductions on landing day probably reflects a p statistical error secondary to reduction of sample size from 16 to 11; average baroreflex slopes were less on landing day than on the 2nd day after landing (3.4 vs. 3.6 ms/mmHg), when reductions were highly significant. The average operational point was significantly lower on landing day than before the mission; therefore reduction of total range of response occurred primarily at the expense of hypotensive buffering capacity. Patients believed to have sinoaortic baroreceptor denervation tend to have supine hypertension as well as orthostatic hypotension (1, 15,25). In the present study, absence of supine hypertension despite putative baroreflex impairment may have reflected other factors, including probable blood volume reductions (16) and increased venous compliance (37). In addition, as inspection of Fig. 3 reveals, virtually all the loss of responsiveness occurred in the hypotensive portion of the stimulus; the hypertensive portion was unchanged.
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VAGAL
BAROREFLEXES
AND
669
SPACEFLIGHT
r ..a? -r” cE 40
-more resistant Bless resistant * = p ( 0.05
systolic FIG.
picted
7. Comparisons of preflight in Fig. 6. *P < 0.01.
n=8 n=6
diastolic
to landing
day changes
between
We emphasize that although most of the changes we documented were significant, they also were subtle and seemed not to impair crew performance during or after these very brief flights. Despite vagally mediated reductions of R-R interval responses suggested by these measurements, crew members were asymptomatic. No subject reported difficulty exiting the Space Shuttle, and no subject exhibited syncope or presyncope during postflight stand tests. However, all subjects had exaggerated heart rate speeding during standing (orthostatic tachycardia) after flight. Because our data document reduced capacity to increase heart rate by withdrawal of vagal 2. Comparisons of more resistant and less resistant subjects TABLE
10 Days Before
Weight, kg Age, Yr
Maximum slope, ms/mmHg R-R range, ms Operational point, % Values
are means
Day
More resistant
Less resistant
More resistant
74.3Ok3.3 42.1t2.4
77.2Ok2.9 43.1k1.8
73.86k3.3
75.76k2.9
Stand Systolic pressure, mmHg Supine Standing Diastolic pressure, mmHg Supine Standing Heart rate, beats/ min Supine Standing R-R interval, ms Supine Standing
Landing
Launch
Less resistant
tests
110.4k3.4 121.4k3.4
106.4k3.0 118.9k2.0
110.3k3.7 124.3k4.0
117.9k3.9 114.0+2.9 -
66.0t3.0 81.0t2.6
68.6t3.2 84.7k2.0
71.8k3.8 87.7k3.4
80.9k3.8 87.7k9.1
58.6k2.3 76.9k3.0
51.3t2.6 66.9t3.0*
67.0t2.4 98.3t3.7
66.7t2.6 104.4t4.2 -
1,032+10 791+10
1,205+11* 912tll*
9Olk9 640t9
931tlO 613t12
Baroreflex
measurements
3.7k1.5 194t9
5.9k2.3” 232+13
3.2k1.2 17728
5.0+2.0* 225212
45.8t3.3
54.4+3.4*
32.4k3.3
27.7t4.1
+ SE for 11 subjects.
* P 5 0.05 between
groups.
2 groups
identified
by cluster
analysis
and de-
outflow, exaggerated cardioacceleration during standing probably was due to increased sympathetic responsiveness. The pattern of astronauts’ responses may be similar to that of a patient described by Rosen and Cryer (32), who had chronic unexplained hypovolemia associated with exaggerated increases of plasma norepinephrine and cardioacceleration with standing. This interpretation is also supported by a study showing that rats experience significantly increased adrenomedullary responses to stress after spaceflight (27). Persistence of reduced vagal responses. Impairment of R-R interval responses to carotid baroreceptor stimulation persisted throughout the period of data collection (8-10 days). Our documentation of protracted impairment of baroreflex function is not without precedent; there is substantial evidence that restoration of normal autonomic function after exposure to weightlessness or simulated weightlessness occurs slowly. After the l40day Salyut-6 mission, cosmonauts had higher plasma catecholamine levels on the 8th day after flight than on landing day (38); after the 237-day Salyut-7 mission, cosmonauts’ plasma catecholamines remained elevated for 25 days after landing (26); and after the M-day Skylab-4 mission, astronauts’ responses to lower body negative pressure did not return to preflight levels until 5-11 days after landing (17). After 30 days of head-down bed rest, subjects’ baroreflex function did not return to normal until after 5 days of ambulation (6). Differences between more resistant and less resistant groups. Astronauts in the group with reduced increases of
systolic pressure during standing also had an (insignificantly) greater cardioacceleration than that of the resistant group. This suggests that the stress of standing was much greater, perhaps resulting from factors other than neural mechanisms. There are several possibilities. Primarily, this group had significantly greater losses of body weight (probably reflecting greater losses of plasma volume) after flight. These data may point toward some interaction between changes of plasma volume and baroreflex function. Second, their postflight operational points were much lower than those of the more resistant group. Thus they had less capacity for early heart rate speeding
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670
VAGAL
BAROREFLEXES
with standing, secondary to vagal withdrawal. Third, impaired vasoconstrictor responses (which we did not study) may also have contributed. Another study (30) of astronauts’ hemodynamic function before and after Space Shuttle flights (which included some of the same subjects we studied) showed that increases of total peripheral resistance with standing are markedly reduced on landing day from preflight levels. We cannot fully explain why astronauts who supported their standing systolic pressures poorly after missions had higher heart rates during standing than those who supported their systolic pressures well. In an earlier study of the effects of head-down bed rest (6), subjects who developed orthostatic intolerance had slower, not faster, heart rates during standing. In the present study, the stand test was short (5 min), and no subjects developed presyncope; if they had, their heart rates would conceivably have slowed after they sped. This speculation is supported by results obtained from patients with vasovagal syncope, in whom inordinate cardioacceleration preceded the occurrence of cardiac slowing and hypotension (39). The preflight differences between these two groups also are very interesting. Although we have no data on the fitness levels of any of our subjects, some of the preflight characteristics of the less resistant group are suggestive of a high level of aerobic fitness. They had significantly greater supine and standing R-R intervals, greater maximum slopes, and higher operational points. Levine et al. (28) showed that highly fit individuals have less orthostatic tolerance than less fit individuals, although their carotid baroreceptor-cardiac reflex response slopes and ranges are not different. In that study the highly fit individuals had significantly higher operational points. Several additional studies reported that highly fit individuals have decreased orthostatic tolerance (23,24,35) and even suggested that a high level of fitness is inadvisable for astronauts (24). The present data lend indirect support to this idea. Mechanisms that may contribute to postflight baroreflex malfunction. We have no sure explanation for our findings. It seems unlikely that baroreflex impairment was caused simply by the blood volume reductions that occur after space missions (16). Baroreflex abnormalities caused by prolonged head-down bed rest develop days after blood volume reductions occur and persist for days after blood volume returns to normal (6). Acute changes in blood volume also do not affect carotid baroreceptorcardiac reflex function (36). In space, afferent neural traffic is probably altered in several ways. Changes of arterial and venous pressures (14, 22) probably alter arterial and cardiopulmonary baroreceptor input, and decreases of left ventricular volume (4,40) probably alter left ventricular receptor firing. Also, aortic and carotid baroreceptor areas may be affected differently by spaceflight. Aortic baroreceptors, because of their more neutral position, are not normally exposed to the same postural pressure changes as the carotid baroreceptors. Therefore exposure to microgravity, where postural changes are lost, may affect aortic and carotid baroreceptors differently. On landing, aortic baroreflexes may be operating more effectively than carotid baroreflexes.
AND
SPACEFLIGHT
Limitations. This study was more difficult to conduct than usual studies involving human subjects, because measurements were made before and after Space Shuttle missions. Changes of sleep-wake cycles, personal exercise regimens, quantity and quality of sleep, and diet (including fluid intake) before and during flights could not be controlled. Other factors, including human use regulations, launch and landing delays, equipment transport difficulties, and competition for subjects’ time also conspired against orderly prosecution of this research. Landing day data are particularly difficult to obtain and interpret; we include these data, however, because of their potentially large practical importance. Our method of baroreceptor stimulation also has limitations. Although -65 mmHg almost always defines saturation pressures, +40-mmHg pressure does not define threshold pressures in all subjects. The subject depicted in Fig. 1 is an example of this. In this study, six of the 16 astronauts had poorly defined minimum R-R intervals preflight. However, only one had a poorly defined threshold on landing day. This is reflected in Fig. 2, which shows a more clearly defined minimum plateau on landing day than preflight. However, in the casesin which the minimum R-R interval is not well defined, both the calculated range and operational point are underestimated, making it more unlikely to discover a postflight reduction in either variable. Thus we believe this limitation does not invalidate the results. Another limitation is that this technique documents changes of vagal baroreflex mechanisms but does not define sympathetic mechanisms. We suspect, but have not proven, that the vagal abnormalities we found are tied in some way to sympathetic abnormalities. Very recent unpublished data show that resting plasma norepinephrine levels, as well as changes in norepinephrine with standing, are increased on landing day (N. Cintron, personal communication). In conclusion, we studied vagally mediated carotid baroreceptor-cardiac reflex responses before and after short Space Shuttle missions. We found subtle but functionally relevant impairment of baroreflex responses that became more marked several days after landing and did not recover by 8-10 days after landing. This study reports the first evidence that baroreflex mechanisms are impaired after spaceflight. We are grateful to the 16 astronauts who donated their valuable time to this effort. They enthusiastically volunteered for this study, which was conducted at times when they had extraordinary mission responsibilities. Without their cooperation this research could not have been done. We also thank Douglas T. F. Simmons for statistical support, Debra F. Lanehart for technical support, and Jay C. Buckey for loan of equipment. This research was supported by National Aeronautics and Space Administration (NASA) Contracts NAS9-17720 and NAS9-16038 and NASA Grant NAG2-408. Address for reprint requests: J. M. Fritsch, Space Biomedical Research Institute, Code SD5, NASA Johnson Space Center, Houston, TX 77058. Received
6 February
1991; accepted
in final
form
16 March
1992.
REFERENCES 1.
AKSAMIT, T.R.,J.S.
FLORAS, R.G. VICTOR,AND P.E. Paroxysmal hypertension due to sinoaortic baroreceptor tion in humans. Hypertension 9: 309-314, 1987.
AYLWARD. denerva-
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VAGAL
BAROREFLEXES
2. ANDERBERG, M. R. Cluster Analysis for Applications. New York: Academic, 1973. 3. BLOMQVIST, C. G., J. V. NIXON, R. L. JOHNSON, JR., AND J. H. MITCHELL. Early cardiovascular adaptation to zero gravity simulated by head-down tilt. Acta Astronaut. 7: 543-553, 1980. 4. BLOMQVIST, C. G., AND H. L. STONE. Cardiovascular adjustments to gravitational stress. In: Handbook of Physiology. The Cardiovascular System. Peripheral Circulation and Organ Blood Flow. Bethesda, MD: Am. Physiol. Sot., 1983, sect. 2, vol. III, part 2, chapt. 28, p. 1025-1063. 5. BUNGO, M. W., AND P. C. JOHNSON, JR. Cardiovascular examinations and observations of deconditioning during the space shuttle orbital flight test program. Aviat. Space Environ. Med. 54: lOOl1004, 1983. 6. CONVERTINO, V. A., D. F. DOERR, D. L. ECKBERG, J. M. FRITSCH, AND J. VERNIKOS-DANELLIS. Head-down bed rest impairs vagal baroreflex responses and provokes orthostatic hypotension. J. Appl. Physiol. 68: 1458-1464, 1990. 7. DIETLEIN, L. F. Skylab: A beginning. In: Biomedical Results from Skylab, edited by R. S. Johnston and L. F. Dietlein. Washington, DC: NASA, 1977, p. 408-418. 8. DRAPER, N. R., AND H. SMITH. Applied Regression Analysis. New York: Wiley, 1981, p. 294-352. 9. ECKBERG, D. L. Respiratory sinus arrhythmia: a window on central autonomic regulation in man. In: The Peripheral Circulation, edited by S. Hunyor, J. Ludbrook, J. Shaw, and M. McGrath. Amsterdam: Elsevier, 1984, p. 267-274. 10. ECKBERG, D. L., V. A. CONVERTINO, J. M. FRITSCH, AND D. F. DOERR. Reproducibility of human vagal carotid baroreceptor-cardisc reflex responses. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): 215-220, 1992. 11. ECKBERG, D. L., AND J. M. FRITSCH. Carotid baroreceptor cardiacvagal responses during 10 days of head-down tilt (Abstract). Physiologist 33, Suppl. 1: S177, 1990. 12. FRITSCH, J. M., R. F. REA, AND D. L. ECKBERG. Carotid baroreflex resetting during drug-induced arterial pressure changes in humans. Am. J. Physiol. 256 (Regulatory Integrative Comp. Physiol. 25): R549-R553, 1989. 13. GIBBONS, J. D. Nonparametric Methods for Quantitative Analysis. New York: Holt, Rinehart and Winston, 1976. 14. HOFFLER, G. W., R. A. WOLTHUIS, AND R. L. JOHNSON. Apollo space crew cardiovascular evaluations. Aerosp. Med. 45: 807-820, 1974. 15. HOLTON, P., AND J. B. WOOD. The effects of bilateral removal of the carotid bodies and denervation of the carotid sinuses in two human subjects. J. Physiol. Lond. 181: 365-378, 1965. 16. JOHNSON, P. C., T. B. DRISCOLL, AND A. D. LEBLANC. Blood volume changes. In: Biomedical Results from Skylab, edited by R. S. Johnston and L. F. Dietlein. Washington, DC: NASA, 1977, p. 235241. 17. JOHNSON, R. L., G. W. HOFFLER, A. E. NICOGOSSIAN, S. A. BERGMAN, JR., AND M. M. JACKSON. Lower body negative pressure: third manned Skylab mission. In: Biomedical Results from Skylab, edited by R. S. Johnston and L. F. Dietlein. Washington, DC: NASA, 1977, p. 284-312. 18. KAKURIN, L. I., V. I. LOBACHIK, V. M. MIKHAILOV, AND Y. A. SENKEVICH. Antiorthostatic hypokinesia as a method of weightlessness simulation. Aviat. Space Environ. Med. 47: 1083-1086, 1976. 19. KASTING, G. A., D. L. ECKBERG, J. M. FRITSCH, AND C. L. BIRKETT. Continuous resetting of the human carotid baroreceptorcardiac reflex. Am. J. Physiol. 252 (Regulatory Integrative Comp. Physiol. 21): R732-R736, 1987. 20. KATONA, P. G., AND F. JIH. Respiratory sinus arrhythmia: noninvasive measure of parasympathetic cardiac control. J. Appl. Physiol. 39: 801-805, 1975. 21. KATONA, P. G., J. W. POITRAS, G. 0. BARNETT, AND B. S. TERRY. Cardiac vagal efferent activity and heart period in the carotid sinus reflex. Am. J. Physiol. 218: 1030-1037, 1970.
AND
SPACEFLIGHT
671
22. KIRSCH, K. A., L. ROCKER, 0. H. GAIJER, R. KRAUSE, C. LEACH, H. J. WICKE, AND R. LANDRY. Venous pressure in man during weightlessness. Science Wash. DC 225: 218-219, 1984. 23. KLEIN, K. E., H. M. WEGMANN, H. BRUNER, AND L. VOGT. Physical fitness and tolerances to environmental extremes. Aerosp. Med. 40: 998-1001, 1969. 24. KLEIN, K. E., H. M. WEGMANN, AND P. KUKLINSKI. Athletic endurance training-advantage for space flight?: The significance of physical fitness for selection and training of spacelab crews. Aviat. Space Environ. Med. 48: 215-222, 1977. 25. KOCHAR, M. S., T. J. EBERT, AND K. J. KOTRLY. Primary dysfunction of the afferent limb of the arterial baroreceptor reflex system in a patient with severe supine hypertension and orthostatic hypotension. J. Am. Col. Cardiol. 4: 802-805, 1984. 26. KVETNANSKY, R., N. A. DAVYDOVA, V. B. NOSKOV, M. VIGAS, I. A. POPOVA, A. C. USAKOV, L. MACHO, AND A. I. GRIGORIEV. Plasma and urine catecholamine levels in cosmonauts during long-term stay on space sation Salyut-7. Acta Astronaut. 17: 181-186, 1988. 27. KVETNANSKY, R., T. TORDA, L. MACHO, R. A. TIGRANIAN, L. SEROVA, AND A. M. GENIN. Effect of weightlessness on sympatheticadrenomedullary activity of rats. Acta Astronaut. 8: 469-481,1981. 28. LEVINE, B. D., J. C. BUCKEY, J. M. FRITSCH, C. W. YANCY, JR., D. E. WATENPAUGH, P. G. SNELL, L. D. LANE, D. L. ECKBERG, AND C. G. BLOMQVIST. Physical fitness and cardiovascular regulation: mechanisms of orthostatic intolerance. J. Appl. Physiol. 70: 112-122,199l. 29. LILLIEFORS, H. W. On the Kolmogorov-Smirnov test for normality with mean and variance unknown. J. Am. Stat. Assoc. 62: 399-402, 1967. 30. MULVAGH, S. L., J. B. CHARLES, S. M. FORTNEY, AND M. W. BUNGO. Changes in peripheral vascular resistance may account for orthostatic intolerance after space flight (Abstract). Circulation 82, Suppl. III: 111-515, 1990. 31. MURRAY, R. H., J. KROG, L. D. CARLSON, AND J. A. BOWERS. CUmulative effects of venesection and lower body negative pressure. Aerosp. Med. 38: 243-247, 1967. 32. ROSEN, S. G., AND P. E. CRYER. Postural tachycardia syndrome. Reversal of sympathetic hyperresponsiveness and clinical improvement during sodium loading. Am. J. Med. 72: 847-850, 1982. 33. SNEDECOR, G. W., AND W. G. COCHRAN. Statistical Methods (6th ed). Ames: Iowa State University Press, 1967. 34. SPRENKLE, J. M., D. L. ECKBERG, R. L. GOBLE, J. J. SCHELHORN, AND H. C. HALLIDAY. Device for rapid quantification of human carotid baroreceptor-cardiac reflex responses. J. Appl. Physiol. 60: 727-732, 1986. 35. STEGEMANN, J., A. BUSERT, AND D. BROCK. Influence of fitness on the blood pressure control system in man. Aerosp. Med. 45: 45-48, 1974. 36. THOMPSON, C. A., D. L. TATRO, D. A. LUDWIG, AND V. A. CONVERTINO. Baroreflex responses to acute changes in blood volume in humans. Am. J. Physiol. 259 (Regulatory Integrative Comp. Physiol. 28): R792-R798, 1990. 37. THORNTON, W. E., G. W. HOFFLER, AND J. A. RUMMEL. Anthropometric changes and fluid shifts. In: Biomedical Results from Skylab, edited by R. S. Johnson and L. F. Dietlein. Washington, DC: NASA, 1977, p. 330-338. 38. TIGRANIAN, R. A., R. KVETNANSKY, N. F. KALITA, N. A. DAVYDOVA, E. A. PAVLOVA, AND L. I. VORONIN. Effect of space flight stress factors on the activity of the sympathetic adrenomedullary and the pituitary-adrenocortical systems. In: Catecholamines and Stress: Recent Advances, edited by E. Usdin, R. Kvetnansky, and I. J. Kopin. New York: Elsevier/North-Holland, 1980, p. 409-421. 39. WAHBHA, M. M. A. E., C. A. MORLEY, Y. M. H. AL-SHAMMA, AND R. HAINSWORTH. Cardiovascular reflex responses in patients with unexplained syncope. Clin. Res. 77: 547-553, 1989. 40. WINTER, D. L. Weightlessness and gravitational physiology. Federation Proc. 36: 1667-1671, 1979.
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JOHN B. CHARLES, BARBARA AND DWAIN L. ECKBERG
S. BENNETT,
Departments of Medicine and Physiology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center and Medical College of Virginia, Richmond, Virginia 23249; Space Biomedical Research Institute, National Aeronautics and Space Administration Johnson Space Center, and KRUG Life Sciences, Hous ton, Texas 77058 FRITSCH,JANICE M., JOHN B. CHARLES,BARBARA S.BENNETT, MICHELE M. JONES, AND DWAIN L. ECKBERG. Shortduration spaceflight impairs human carotid baroreceptor-cardiac reflex responses. J. Appl. Physiol. 73(2): 664-671,1992.-Orthostatic intolerance is a predictable but poorly understood consequence of space travel. Because arterial baroreceptors modulate abrupt pressure transients, we tested the hypothesis that spaceflight impairs baroreflex mechanisms. We studied vagally mediated carotid baroreceptor-cardiac reflex responses (provoked by neck pressure changes) in the supine position and heart rate and blood pressure in the supine and standing positions in 16 astronauts before and after 4- to s-day Space Shuttle missions. On landing day, resting R-R intervals and standard deviations, and the slope, range, and position of operational points on the carotid transmural pressure-sinus node response relation were all reduced relative to preflight. Stand tests on landing day revealed two separate groups (one maintained standing arterial pressure better) that were separated by preflight slopes, operational points, and supine and standing R-R intervals and by preflight-to-postflight changes in standing pressures, body weights, and operational points. Our results suggest that short-duration spaceflight leads to significant reductions in vagal control of the sinus node that may contribute to, but do not account completely for, orthostatic intolerance. microgravity;
orthostatic;
vagal
EXPOSURETOWEIGHTLESSNESS alterspostflightcardiovascular responses to exercise and standing. Although these changes are probably initiated during flight, they are not known to impair cardiovascular performance in space (7). However, functional problems become apparent on landing, when most astronauts have reduced exercise capacity and orthostatic tolerance (5). The cause of orthostatic intolerance is unclear. Loss of plasma volume during weightlessness (16) may be partly responsible. However, acute comparable blood volume reductions usually do not provoke orthostatic hypotension (32), and repletion of blood volume after simulated weightlessness does not completely prevent orthostatic hypotension (3). This study explores a possibility, suggested by groundbased research, that impairment of normal baroreflex mechanisms contributes to postweightlessness orthostatic intolerance. Head-down tilt [a widely used simulation of weightlessness (18)] reduces R-R interval responses to carotid baroreceptor stimulation (6, 11); in
one study (6), such reductions were correlated directly with the magnitude of post-bed-rest blood pressure reductions during standing. We studied vagally mediated baroreceptor-cardiac reflex responses of American astronauts before and after Space Shuttle missions lasting 4-5 days and correlated baroreflex responses with blood pressure and heart rate responses to standing. Our results suggest that spaceflight reduces baseline levels of vagal-cardiac outflow and vagally mediated responses to changes of arterial baroreceptor input. Furthermore, our data suggest that these changes contribute to postflight reductions of astronauts’ ability to maintain standing arterial pressures. MATERIALS
AND METHODS
Subjects and protocol. We studied 16 astronauts (15 males and 1 female), whose average age was 43 t 4 (SE) yr (range 36-54 yr), before and after Space Shuttle missions lasting 4-5 days. Our protocol was approved by the Johnson Space Center Human Research Policies and Procedures Committee and the Human Research Committees of the Hunter Holmes McGuire Department of Veterans Affairs Medical Center and the Medical College of Virginia. Preflight studies were performed nominally 10 and 5 days before launch; in practice, preflight data were collected between 13 and 7 days and again between 7 and 5 days before launch. Acceptable postflight data were collected on landing day (n = ll), on the 2nd and 3rd days after landing (n = 16), and on postflight days 8, 9, or 10 (n = 12). The electrocardiogram, respiration (abdominal bellows connected to a strain gauge pressure transducer), and neck chamber pressure were recorded by FM tape and strip chart recorders. The electrocardiogram and respiration were recorded during the last 5 min of a 20-min rest period before any intervention. Resting vagal-cardisc activity was estimated from average R-R intervals and their standard deviations (9,20). Blood pressure was measured manually with a sphygmomanometer before baroreceptor testing. Several aspects of this experiment were beyond our control. Eight crew members shifted their sleep-wake cycles in preparation for flight and took sleeping medications (flurazepam HCl, Roche; or temazepam, Sandoz)
664 Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (143.088.066.066) on August 25, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
VAGAL
pressure, ~~;g
BAROREFLEXES
AND
665
SPACEFLIGHT
4i[l%% -65
R-R interval, msec
1400 1000 [ +
-
electrocardiogram FIG. 1. Original record showing neck sequence and responses of 1 subject (A) of that subject’s average responses to 7 sequences (B). Closed circle, operational
0-O 0
\
/
0 \
slope = 7.4 msec/mmHg
I I I I I 1.
P 0
0
carotid
50
0 I
/
pressure minimum
I I
I
I
100
150
distendina
T I I 1
01 range = 339 msec
I
minimum R-R
pressure and plot stimulus point.
J
at R-R I
200
w-essure, I
the night before the second preflight measurement (-5 days before launch); three crew members took temazepam within 24 h before landing. Data obtained on days after these medications were taken were discarded. For all other subjects, measurements made nominally 10 and 5 days before launch were averaged to obtain control values. We were unable to collect data on two subjects on landing day because of equipment malfunction. Baroreflex stimuli. After the rest period, a tightly sealing Silastic chamber was strapped to the anterior neck (35). A computer-controlled stepping motor-driven bellows delivered a fixed sequence of pressure and suction steps to the chamber during held expiration, as follows. Pressure was increased to ~40 mmHg for ~5 s, reduced by -15-mmHg decrements after each of the next seven R waves to about -65 mmHg, and finally returned to ambient levels. Responses from seven successful repetitions of this stimulus sequence during each experimental session were averaged. R-R intervals were plotted against carotid distending pressures (taken to be systolic minus neck chamber pressures). Figure 1 is an original record showing a neck pressure sequence and response of one subject and a plot of that subject’s average response to seven stimulus sequences. Earlier studies showed that these stimuli and baroreflex responses are highly reproducible (10, 19).
250
mmHg Prior studies (12,19) also showed that when data from such baroreflex stimuli are fitted to a four-parameter logistic equation, confidence limits are so large that derived equations do not describe the data accurately. Therefore, in this study baroreflex response relations were reduced to other parameters for analysis, including minimum, maximum, and range of R-R interval responses, carotid distending pressures at minimum and maximum R-R intervals, maximum slopes, and operational points. Maximum slopes were identified with linear regression analyses applied to each set of three consecutive pairs of data on the stimulus-response relation. Operational points were defined as [(R-R intervals at 0 mmHg neck pressure - minimum R-R intervals)/R-R interval range] X 100%. The operational point is a measure of the relative baroreflex buffering capacity for pressures above and below resting levels. (Thus when operational points are low, there is less relative buffering capacity for the hypotensive part of the stimulus, and when operational points are high, there is less relative buffering capacity for the hypertensive part of the stimulus.) The operational point has constraints because of the nature of the stimulus profile. This profile, the limits of which are defined by subject tolerance, fails to define a plateau at the minimum R-R interval in -20% of subjects. A true threshold cannot be defined in these sub-
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666
VAGAL
BAROREFLEXES
jects, and the operational point as calculated is not the true operational point of a classic sigmoid curve. We use it only to define the relative capacity to buffer the hypotensive portion of the stimulus profile we deliver. If that same stimulus is delivered before and after interventions, the operational point provides useful information. Stand test. Stand tests were performed on all subjects 10 days before launch, on landing day, and 3 days after landing. Blood pressure, measured manually with a sphygmomanometer, and heart rates were measured every minute for 10 consecutive min (5 during supine rest, 1 immediately after standing, and 4 during standing with subjects leaning against a wall with their heels 6 in. from the wall). The five supine blood pressures and heart rates were averaged to derive supine measurements. The maximum standing heart rate and its corresponding blood pressure were taken as the standing measurement. We used R-R intervals in these analyses because the relation between changes of R-R intervals and those of vagal-cardiac traffic is linear (21). The relation between heart rate and vagal-cardiac traffic is curvilinear; this makes comparisons before and after interventions difficult if baseline heart rate has changed. Fluid loading. All 16 subjects followed some fluid loading protocol before reentry. Most took salt tablets or salty food and 21 liter of water or juice. Many consumed 21 liter of fluid. All crew members had access to unlimited fluids between the time they exited the orbiter and entered the clinic where the studies were performed (12 h after landing). Statistics. All data are means t SE. Because some measured variables were not distributed normally (29), nonparametric statistical tests were used. We used the Wilcoxon signed-rank test (33) to identify differences among results obtained during experimental sessions and the Spearman test (13) to identify correlations among measurements. We applied cluster analysis (2) to identify groups according to blood pressure responses on landing day. Forward selection, backward elimination, and stepwise regression modeling methods (8) were used to predict changes of standing minus supine systolic pressure on landing day. The following factors were entered into the model as independent variables: maximum baroreflex slope and R-R interval range, operational point, and body weight. The entry level significance for these independent variables was set at P = 0.25. Results from forward selection and backward elimination methods were similar, and therefore only results from backward elimination analyses are presented. P < 0.05 was considered significant. RESULTS
Preflight reproducibility. Baroreflex responses measured 10 and 5 days before flight were not different. The range of R-R interval responses averaged 237 t 52 and 250 t 36 ms (P = 0.82), respectively, and the maximum slope averaged 5.0 t 0.8 and 5.0 t 0.7 ms/mmHg (P = 0.59). Because the two preflight measurements were so reproducible, they were averaged to derive preflight values. Control measurements. Average baseline measure-
AND
SPACEFLIGHT
ments for all subjects are given in Table 1. Baseline arterial pressure did not change throughout the study. Resting R-R intervals, their standard deviations, and body weight were all significantly reduced, but on landing day only. Baroreflex responses. Average R-R interval responses to carotid baroreceptor stimuli for all subjects are presented in Table 1, and responses measured on landing and subsequent days are shown in Figs. 2-4. Average slopes and ranges were reduced insignificantly on landing day and significantly on postflight days Z-10. On landing day (Fig. 2), the response relation was lower on the R-R interval axis (as reflected by minimum and maximum R-R intervals) but at the same position on the pressure axis (as reflected by carotid distending pressures at minimum and maximum R-R intervals). Also on landing day, maximum slopes and ranges were reduced in about one-half of the subjects, and the position of the operational point was reduced in 86% of them. By the 2nd day after landing (Table 1, Fig. 3), the average baroreflex slope and range were significantly reduced, but the operational point had returned to the preflight level. Compared with preflight levels, 60% of subjects had reduced slopes, 75% had reduced ranges, and 69% had lower operational points. By this time the average minimum, but not maximum, R-R intervals had returned toward a higher point on the R-R interval axis. The position of the response relation on the pressure axis still was not different from preflight. On the 3rd day after landing and thereafter (Table 1, Fig. 4), the average R-R interval slope and range remained significantly reduced. The average maximum RR interval was reduced on days 8-10. All other parameters were comparable to preflight values. Stand tests. Changes of systolic and diastolic pressures and heart rates on standing for all subjects are shown in Fig. 5. Preflight increases of systolic and diastolic pressures with standing were 11 ? 3 (107 t 3 to 118 t 1) and 15 + 3 (68 + 2 to 83 + 1) mmHg. The preflight maximum increase ofheart rate with standing was 16 t 1 (55 t 2 to 71 -+ 1) beats/min. On landing day, average increases of systolic and diastolic pressure were 5 t 3 (115 t 3 to 120 t 3, P = 0.04 f rom preflight) and 12 t 2 (76 t 3 to 88 t 2, P = 0.13) mmHg. Heart rate increases from supine to standing positions averaged 31 t 3 (65 t 7 to 96 t 4, P = 0.0008, from preflight) beats/min on landing day and were significantly larger than preflight values. Heart rate responses also were converted to R-R intervals for analysis. Decreases of R-R intervals with standing averaged 254 t 32 ms (1,113 t 35 to 859 t 30) before launch and 293 t 29 ms (933 t 29 to 640 t 28) on landing day (P = 0.052 from preflight). Correlations
between
stand
tests and baroreflex
data.
Systolic pressure responses to standing varied among subjects on landing day. Cluster analysis of these changes identified two groups of astronauts (r = 0.68, P < 0.01). Figure 6 illustrates the results of this analysis. One group maintained standing systolic pressures well, and the other did not. Responses of these two groups to standing are shown in Fig. 7. Comparisons between the two groups are shown in Table 2. In subjects who main-
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VAGAL TABLE
BAROREFLEXES
667
AND SPACEFLIGHT
1. Measurements from all subjects on all test days Postflight Preflight
Systolic pressure, mmHg Diastolic pressure, mmHg R-R interval, ms Standard deviation of R-R, ms Body weight, kg
Landing
2
3
8-10
116+2 75+1 1,123&42
116+2 73t2 965+25*
117t2 72k2 1,069+38
116t2 73k2 1,134-t39
116k2 74k2 1,069+31
62t6 75.6k4.0
40t4* 74.4t2.4*
58t6 75.2k2.4
55k5 75.3t2.4
47+5 75.4k2.1
3.6t0.6* 39.8k3.6
3.9t0.6* 52.4k4.7
3.9+0.6* 42.4k6.0
177+20* 1,213&41*
192+102* 1,084+35 1,275*43
189&27* 1,037+31 1,226*38*
92k9 160t6
82k7 157+7
75k2 161k5
Baroreflex
Maximum slope, ms/mmHg Operational point, % R-R interval, ms Range Minimum Maximum Carotid distending pressure, mmHg At minimum R-R At maximum R-R
Day
Day
measurements
5.Okl.O 48.9k3.5 243k47 1,081+43 1,324-+68
3.4t0.5 29.4+4.2-f 182k25 923k30” 1,104*31*
8Ok4 153t-8
1,036+39
83k4 172t4
Values are means + SE. All comparisons between landing day and preflight measurements used only 11 subjects; those between landing day and measurements taken 8-10 days after landing used only 12 subjects. * P < 0.05; t P -c 0.01. 1450
1450< E
0
y350
preflight
1250
T/ A
k-AHTA
T
-A
T
Al/A CY I (y
N
950
T/
3 .r
.,6-h T/ 0
landing day n=
oc I
11
rY
Tf T,A TA A’ 0-y 1
1050
carotid
100
distending
150
200
pressure,
mmHg
FIG. 2. Carotid baroreceptor vagal-cardiac reflex responses before flight and on landing day. Closed symbols, position of operational points. Average operational point was reduced significantly on landing day, but slope and range were not.
tained systolic pressure well, the average increase of systolic pressure with standing was 3 t 2 mmHg greater on landing day than before flight (systolic pressure increased from 110 to 121 mmHg before flight and from 110to 124 on landing day). In the other group of subjects, systolic pressure actually fell with standing on landing day so that it was actually 17 t 3 mmHg less on landing day than before flight. This difference between groups was significant (P = 0.0001). The two groups also differed significantly in preflight-to-postflight standing minus supine increases of diastolic pressure (0.9 t 3.9 vs. -9.3 t 4.6 mmHg, P = 0.031), preflight to postflight reductions of their operational points (-13.4 t 3.0 vs. -26.7 t 4.7%, P = 0.0005), and weight lost during the flight (-0.44 t 1.3 vs. -1.44 t 0.5 kg, P = 0.0001). Results from backward elimination analysis showed that preflight-to-postflight changes of standing minus supine systolic pressures on landing day were predicted primarily by preflight-to-postflight changes of operational point (P = 0.0041) and of body weight (P = 0.034). The R value for the model was 0.64 (P = 0.0034). No
/c:
MO 1
@
100 1
50
carotid
distending
.0-y-o *
-A
1
l
950 850
50
A-A.
A-
Y
i 850)
1
TTkT
z1150
I
n=16
-1250
A T,o
1
1
preflight sloDe=5.0 4 m&c/mmHg
E
rf
T/
1
landing + 2 slope=3.6 msec/mmHg I
I
150
200
pressure,
mmHg
FIG. 3. Carotid baroreceptor vagal-cardiac reflex responses before flight and 2 days after landing. Average slope and range were significantly reduced, but operational point (closed symbols) was not.
other variables (preflight or postflight) contributed to the model. The differences between the two groups extended to some preflight measurements. These differences are described in Table 2. Before flight the less resistant group had greater supine and standing R-R intervals and slower standing heart rates. Resting heart rates were also slower, although not significantly. In addition, the less resistant group had significantly larger slopes of the baroreflex response and significantly higher operational points. On landing day, baseline, minimum, and maximum RR intervals correlated directly with heart rate responses to standing (P = 0.003, 0.050, and 0.005, respectively). Slopes and ranges did not correlate with any variable measured during the stand test. By the 3rd day after landing, stand test responses were not different from preflight values. Heart rate increases with standing averaged 18 t 2 (55 t 2 to 73 t 3, P = 0.014) beats/min, and systolic and diastolic increases with standing averaged 5 t 2 (112 t 2 to 117 t 2, P = 0.78) and 12 t 2 (69 t 2 to 81 t 1, P = 0.95) mmHg. The
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668
VAGAL
BAROREFLEXES
AND
SPACEFLIGHT
n = 14 r = 0.68 p ( 0.01
0
H E
u-
-60
0
250
I 10I
I
1
I
,
preflight 4. Average *P < 0.05.
slopes,
landing ranges,
0 *
1
2
1
4
,
6(8-10)
post-flight
and operational
days points
throughout
average R-R interval was reduced 287 t 25 (1,131 t 50 to 844 t 38) ms on standing on this day. The group differences noted on landing day were no longer evident. DISCUSSION
We delivered a profile of neck pressure and suction changes to 16 American astronauts before and after brief (4 to s-day) Space Shuttle missions to test the hypothesis that space travel impairs human carotid baroreceptor-cardiac reflex responses. This study documents sig40 m El
n=
= preflight = landing
.-t
day
E 30% 4 ii n
16
20 2 F 1oY iii L systolic
change, FIG.
supine ference
diastolic
standing
heart
minus
rate
Oa
supine
5. Preflight and postflight differences between standing systolic and diastolic pressures and heart rate. Significant between groups: *P < 0.05; **P < 0.01.
0
change
point,
I
20 in
%
FIG. 6. Preflight-to-postflight (landing day) changes of operational points and systolic pressure responses to standing. Linear regression correlation coefficients are for all data. Cluster analysis (see MATERIALS AND METHODS) of these data identified 2 distinct groups, which we have termed less and more resistant to postural change. Hatched area, more resistant group.
1-
0 -o’*
-20
to postflight
operational
1
FIG.
-40
pre-
\
study.
“‘-40--
and dif-
n&ant postflight reductions of estimated baseline vagal-cardiac traffic and operational points on landing day and persistent reductions in slope and range of the carotid baroreceptor-cardiac reflex response. Cluster analysis suggested that the astronauts could be divided into two groups according to how well they maintained standing systolic pressure on landing day. These groups were also significantly different in other respects. Astronauts who supported their systolic pressures poorly on landing day had slower heart rates and greater gain of vagally mediated baroreflex responses preflight and greater weight loss and reductions of baroreflex operational points postflight than astronauts who supported pressures well. Vagal responseson landing day. Several measurements point toward reductions of baseline vagal-cardiac traffic and vagally mediated responses to changes of baroreceptor input on landing day. Average baseline R-R interval and standard deviations were less. Average baseline heart rate was significantly greater, and average baroreflex gain and R-R interval range were insignificantly less than preflight. Lack of statistical significance of baroreflex slope and range reductions on landing day probably reflects a p statistical error secondary to reduction of sample size from 16 to 11; average baroreflex slopes were less on landing day than on the 2nd day after landing (3.4 vs. 3.6 ms/mmHg), when reductions were highly significant. The average operational point was significantly lower on landing day than before the mission; therefore reduction of total range of response occurred primarily at the expense of hypotensive buffering capacity. Patients believed to have sinoaortic baroreceptor denervation tend to have supine hypertension as well as orthostatic hypotension (1, 15,25). In the present study, absence of supine hypertension despite putative baroreflex impairment may have reflected other factors, including probable blood volume reductions (16) and increased venous compliance (37). In addition, as inspection of Fig. 3 reveals, virtually all the loss of responsiveness occurred in the hypotensive portion of the stimulus; the hypertensive portion was unchanged.
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VAGAL
BAROREFLEXES
AND
669
SPACEFLIGHT
r ..a? -r” cE 40
-more resistant Bless resistant * = p ( 0.05
systolic FIG.
picted
7. Comparisons of preflight in Fig. 6. *P < 0.01.
n=8 n=6
diastolic
to landing
day changes
between
We emphasize that although most of the changes we documented were significant, they also were subtle and seemed not to impair crew performance during or after these very brief flights. Despite vagally mediated reductions of R-R interval responses suggested by these measurements, crew members were asymptomatic. No subject reported difficulty exiting the Space Shuttle, and no subject exhibited syncope or presyncope during postflight stand tests. However, all subjects had exaggerated heart rate speeding during standing (orthostatic tachycardia) after flight. Because our data document reduced capacity to increase heart rate by withdrawal of vagal 2. Comparisons of more resistant and less resistant subjects TABLE
10 Days Before
Weight, kg Age, Yr
Maximum slope, ms/mmHg R-R range, ms Operational point, % Values
are means
Day
More resistant
Less resistant
More resistant
74.3Ok3.3 42.1t2.4
77.2Ok2.9 43.1k1.8
73.86k3.3
75.76k2.9
Stand Systolic pressure, mmHg Supine Standing Diastolic pressure, mmHg Supine Standing Heart rate, beats/ min Supine Standing R-R interval, ms Supine Standing
Landing
Launch
Less resistant
tests
110.4k3.4 121.4k3.4
106.4k3.0 118.9k2.0
110.3k3.7 124.3k4.0
117.9k3.9 114.0+2.9 -
66.0t3.0 81.0t2.6
68.6t3.2 84.7k2.0
71.8k3.8 87.7k3.4
80.9k3.8 87.7k9.1
58.6k2.3 76.9k3.0
51.3t2.6 66.9t3.0*
67.0t2.4 98.3t3.7
66.7t2.6 104.4t4.2 -
1,032+10 791+10
1,205+11* 912tll*
9Olk9 640t9
931tlO 613t12
Baroreflex
measurements
3.7k1.5 194t9
5.9k2.3” 232+13
3.2k1.2 17728
5.0+2.0* 225212
45.8t3.3
54.4+3.4*
32.4k3.3
27.7t4.1
+ SE for 11 subjects.
* P 5 0.05 between
groups.
2 groups
identified
by cluster
analysis
and de-
outflow, exaggerated cardioacceleration during standing probably was due to increased sympathetic responsiveness. The pattern of astronauts’ responses may be similar to that of a patient described by Rosen and Cryer (32), who had chronic unexplained hypovolemia associated with exaggerated increases of plasma norepinephrine and cardioacceleration with standing. This interpretation is also supported by a study showing that rats experience significantly increased adrenomedullary responses to stress after spaceflight (27). Persistence of reduced vagal responses. Impairment of R-R interval responses to carotid baroreceptor stimulation persisted throughout the period of data collection (8-10 days). Our documentation of protracted impairment of baroreflex function is not without precedent; there is substantial evidence that restoration of normal autonomic function after exposure to weightlessness or simulated weightlessness occurs slowly. After the l40day Salyut-6 mission, cosmonauts had higher plasma catecholamine levels on the 8th day after flight than on landing day (38); after the 237-day Salyut-7 mission, cosmonauts’ plasma catecholamines remained elevated for 25 days after landing (26); and after the M-day Skylab-4 mission, astronauts’ responses to lower body negative pressure did not return to preflight levels until 5-11 days after landing (17). After 30 days of head-down bed rest, subjects’ baroreflex function did not return to normal until after 5 days of ambulation (6). Differences between more resistant and less resistant groups. Astronauts in the group with reduced increases of
systolic pressure during standing also had an (insignificantly) greater cardioacceleration than that of the resistant group. This suggests that the stress of standing was much greater, perhaps resulting from factors other than neural mechanisms. There are several possibilities. Primarily, this group had significantly greater losses of body weight (probably reflecting greater losses of plasma volume) after flight. These data may point toward some interaction between changes of plasma volume and baroreflex function. Second, their postflight operational points were much lower than those of the more resistant group. Thus they had less capacity for early heart rate speeding
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670
VAGAL
BAROREFLEXES
with standing, secondary to vagal withdrawal. Third, impaired vasoconstrictor responses (which we did not study) may also have contributed. Another study (30) of astronauts’ hemodynamic function before and after Space Shuttle flights (which included some of the same subjects we studied) showed that increases of total peripheral resistance with standing are markedly reduced on landing day from preflight levels. We cannot fully explain why astronauts who supported their standing systolic pressures poorly after missions had higher heart rates during standing than those who supported their systolic pressures well. In an earlier study of the effects of head-down bed rest (6), subjects who developed orthostatic intolerance had slower, not faster, heart rates during standing. In the present study, the stand test was short (5 min), and no subjects developed presyncope; if they had, their heart rates would conceivably have slowed after they sped. This speculation is supported by results obtained from patients with vasovagal syncope, in whom inordinate cardioacceleration preceded the occurrence of cardiac slowing and hypotension (39). The preflight differences between these two groups also are very interesting. Although we have no data on the fitness levels of any of our subjects, some of the preflight characteristics of the less resistant group are suggestive of a high level of aerobic fitness. They had significantly greater supine and standing R-R intervals, greater maximum slopes, and higher operational points. Levine et al. (28) showed that highly fit individuals have less orthostatic tolerance than less fit individuals, although their carotid baroreceptor-cardiac reflex response slopes and ranges are not different. In that study the highly fit individuals had significantly higher operational points. Several additional studies reported that highly fit individuals have decreased orthostatic tolerance (23,24,35) and even suggested that a high level of fitness is inadvisable for astronauts (24). The present data lend indirect support to this idea. Mechanisms that may contribute to postflight baroreflex malfunction. We have no sure explanation for our findings. It seems unlikely that baroreflex impairment was caused simply by the blood volume reductions that occur after space missions (16). Baroreflex abnormalities caused by prolonged head-down bed rest develop days after blood volume reductions occur and persist for days after blood volume returns to normal (6). Acute changes in blood volume also do not affect carotid baroreceptorcardiac reflex function (36). In space, afferent neural traffic is probably altered in several ways. Changes of arterial and venous pressures (14, 22) probably alter arterial and cardiopulmonary baroreceptor input, and decreases of left ventricular volume (4,40) probably alter left ventricular receptor firing. Also, aortic and carotid baroreceptor areas may be affected differently by spaceflight. Aortic baroreceptors, because of their more neutral position, are not normally exposed to the same postural pressure changes as the carotid baroreceptors. Therefore exposure to microgravity, where postural changes are lost, may affect aortic and carotid baroreceptors differently. On landing, aortic baroreflexes may be operating more effectively than carotid baroreflexes.
AND
SPACEFLIGHT
Limitations. This study was more difficult to conduct than usual studies involving human subjects, because measurements were made before and after Space Shuttle missions. Changes of sleep-wake cycles, personal exercise regimens, quantity and quality of sleep, and diet (including fluid intake) before and during flights could not be controlled. Other factors, including human use regulations, launch and landing delays, equipment transport difficulties, and competition for subjects’ time also conspired against orderly prosecution of this research. Landing day data are particularly difficult to obtain and interpret; we include these data, however, because of their potentially large practical importance. Our method of baroreceptor stimulation also has limitations. Although -65 mmHg almost always defines saturation pressures, +40-mmHg pressure does not define threshold pressures in all subjects. The subject depicted in Fig. 1 is an example of this. In this study, six of the 16 astronauts had poorly defined minimum R-R intervals preflight. However, only one had a poorly defined threshold on landing day. This is reflected in Fig. 2, which shows a more clearly defined minimum plateau on landing day than preflight. However, in the casesin which the minimum R-R interval is not well defined, both the calculated range and operational point are underestimated, making it more unlikely to discover a postflight reduction in either variable. Thus we believe this limitation does not invalidate the results. Another limitation is that this technique documents changes of vagal baroreflex mechanisms but does not define sympathetic mechanisms. We suspect, but have not proven, that the vagal abnormalities we found are tied in some way to sympathetic abnormalities. Very recent unpublished data show that resting plasma norepinephrine levels, as well as changes in norepinephrine with standing, are increased on landing day (N. Cintron, personal communication). In conclusion, we studied vagally mediated carotid baroreceptor-cardiac reflex responses before and after short Space Shuttle missions. We found subtle but functionally relevant impairment of baroreflex responses that became more marked several days after landing and did not recover by 8-10 days after landing. This study reports the first evidence that baroreflex mechanisms are impaired after spaceflight. We are grateful to the 16 astronauts who donated their valuable time to this effort. They enthusiastically volunteered for this study, which was conducted at times when they had extraordinary mission responsibilities. Without their cooperation this research could not have been done. We also thank Douglas T. F. Simmons for statistical support, Debra F. Lanehart for technical support, and Jay C. Buckey for loan of equipment. This research was supported by National Aeronautics and Space Administration (NASA) Contracts NAS9-17720 and NAS9-16038 and NASA Grant NAG2-408. Address for reprint requests: J. M. Fritsch, Space Biomedical Research Institute, Code SD5, NASA Johnson Space Center, Houston, TX 77058. Received
6 February
1991; accepted
in final
form
16 March
1992.
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AYLWARD. denerva-
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