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Am J Physiol Heart Circ Physiol 288: H839-H847, 2005. First published October 14, 2004; doi:10.1152/ajpheart.00220.2004
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Plasma volume restoration with salt tablets and water after bed rest prevents orthostatic hypotension and changes in supine hemodynamic and endocrine variables

Wendy W. Waters,1 Steven H. Platts,2 Brett M. Mitchell,2 Peggy A. Whitson,3 and Janice V. Meck4

1Human Adaptation and Countermeasures Office, Wyle Laboratories, Inc.; 2Division of Space Life Sciences, Universities Space Research Association; and 3Astronaut Office and 4Human Adaptation and Countermeasures Office, National Aeronautics and Space Administration Johnson Space Center, Houston, Texas

Submitted 5 March 2004 ; accepted in final form 6 October 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Head-down bed rest changes the values of many cardiovascular and endocrine variables and also elicits significant hypovolemia. Because previous studies had not controlled for hypovolemia, it is unknown whether the reported changes were primary effects of bed rest or secondary effects of bed rest-induced hypovolemia. We hypothesized that restoring plasma volume with salt tablets and water after 12 days of head-down bed rest would result in an absence of hemodynamic and endocrine changes and a reduced incidence of orthostatic hypotension. In 10 men, we measured changes from pre-bed-rest to post-bed-rest in venous and arterial pressures; heart rate; stroke volume; cardiac output; vascular resistance; plasma norepinephrine, epinephrine, vasopressin, renin activity (PRA), and aldosterone responses to different tilt levels (0°, –10°, 20°, 30°, and 70°); and plasma volume and platelet {alpha}2- and lymphocyte {beta}2-adrenoreceptor densities and affinities (0° tilt only). Fluid loading at the end of bed rest restored plasma volume and resulted in the absence of post-bed-rest orthostatic hypotension and changes in supine hemodynamic and endocrine variables. Fluid loading did not prevent post-bed-rest increases in {beta}2-adrenoreceptor density or decreases in the aldosterone-to-PRA ratio (P = 0.05 for each). Heart rate, epinephrine, and PRA responses to upright tilt after bed rest were increased (P < 0.05), despite the fluid load. These results suggest that incidents of orthostatic hypotension and many of the changes in supine hemodynamic and endocrine variables in volume-depleted bed-rested subjects occur secondarily to the hypovolemia. Despite normovolemia after bed rest, {beta}2-adrenoreceptors were upregulated, and heart rate, epinephrine, and PRA responses to tilt were augmented, indicating that these changes are independent of volume depletion.

simulated microgravity; cardiovascular; hypovolemia; cardiopulmonary-arterial baroreceptor reflex interaction; adrenergic receptors

HEAD-DOWN BED REST elicits many cardiovascular changes that are similar to those elicited by spaceflight and is commonly accepted as a ground-based analog of spaceflight. The two most consistently reported effects of bed rest are hypovolemia (2, 9–12, 18, 22, 23, 28, 34, 49, 54) and orthostatic intolerance (2, 9–12, 22, 23, 28, 34, 47–49). The intolerance is severe enough to result in orthostatic hypotension in ~49% of bed-rested subjects (2, 9, 23, 34, 48, 49). Many bed-rest studies have pursued the mechanisms of orthostatic hypotension and have documented changes in hemodynamic and endocrine parameters. After bed rest, in a resting state, there have been reported reductions in venous return (10, 18, 21, 47) and increases in heart rate (9, 11, 22, 47, 48) and vascular resistance (12, 13, 22, 28) compared with measurements before bed rest. Reported changes in endocrine parameters after bed rest are somewhat equivocal, but most reports indicate an enhanced renin-angiotensin-aldosterone system (11, 34, 49, 54) and a reduced or unaltered norepinephrine release (1, 9–12, 18). After bed rest, in response to orthostatic stress, there are reductions in stroke volume (2, 10, 28, 38) and arterial pressure (54), increases in heart rate (10, 23, 38, 48, 54), and an enhanced renin-angiotensin-aldosterone system (34, 54) compared with responses before bed rest. Collectively, these changes from pre-bed-rest to post-bed-rest have been used to explain, in part, the etiology of orthostatic hypotension after bed rest; however, these changes also can occur in response to hypovolemia (21, 24, 39). None of the above-mentioned studies reported a correction of hypovolemia before measurements were collected after bed rest. To our knowledge, hypovolemia after bed rest was reduced (to within 4% of pre-bed-rest value) in only one study, but changes from pre-bed-rest to post-bed- rest in resting values were reported in only three variables: central venous pressure and stroke volume (reductions in both) and plasma norepinephrine levels (unchanged) (53). Consequently, despite the abundance of bed-rest studies, two questions never have been satisfactorily answered: 1) Would correction of plasma volume reduce the incidence of orthostatic hypotension after bed rest? 2) Would changes in hemodynamic and endocrine variables, seen after bed rest, be present if plasma volume was corrected? Accordingly, the purpose of this study was to test the hypothesis that oral administration of salt tablets and water to subjects before the end of 12 days of bed rest, at a dose equivalent to that given to astronauts before Shuttle landings, will reduce the incidence of orthostatic hypotension and result in the absence of hemodynamic and endocrine changes after bed rest.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. This protocol was approved by the Johnson Space Center Institutional Review Board, and all subjects gave their written informed consent. Ten healthy, normotensive, nonsmoking men (29 ± 2 yr of age) were studied before and after 12 days of –6° head-down bed rest. Before testing, all subjects exercised regularly, but none were endurance athletes. From 24 h before pre-bed-rest testing through the end of the study, subjects abstained from caffeine, alcohol, medications, and exercise. Subjects were ≥2 h postprandial before each testing session. For the entire hospital stay, subjects received a standard, caffeine-free diet with no limitation of food intake. Dietary sodium intake was ≥4 g (174 meq) per day [similar to average inflight dietary sodium intake in Shuttle and Mir astronauts of 4 g/day (25)], and fluid intake was ad libitum.

Peripherally inserted central catheter. On the day before pre-bed-rest testing, subjects were admitted to the hospital, and a central catheter was inserted into the basilic vein of the right arm for central venous pressure measurement via a cannula connected to a Statham pressure transducer. Fluoroscopy was used to verify placement of the catheter into the superior vena cava after initial insertion and when necessary throughout the study. The central catheter remained in place and was maintained for the entire study.

Protocol. Pre-bed-rest measurements began at 0800 on the following morning. Subjects were orally hydrated with water at 5 ml/kg and then weighed. An indwelling, intravenous catheter was inserted into the antecubital vein of the left arm for blood draws. The subjects were instrumented for electrocardiogram, manual blood pressure, and beat-to-beat finger blood pressure (Finapres, Ohmeda, Louisville, CO). An arm board was attached to the tilt table so that the finger with the continuous arterial pressure device was held at heart level at all levels of tilt. The subjects rested supine for 20 min (stabilization period). Then a blood sample was drawn for measurement of plasma norepinephrine, epinephrine, arginine vasopressin, aldosterone, renin activity, and platelet {alpha}2- and lymphocyte {beta}2-adrenoreceptor densities and affinities. Next, plasma volume was determined using CO rebreathing. Briefly, the subjects breathed 100% O2 on a closed circuit for 2 min. Then 60 ml of CO were injected into the circuit over three inhalations; the subject continued to breathe the O2-CO mixture for 10 min. Before and after CO injection, blood samples were drawn for measurement of carboxyhemoglobin, hematocrit, and hemoglobin. From these measurements, red blood cell volume, blood volume, and plasma volume were calculated. The CO-rebreathing method is a sensitive and precise method that shows a 99% correlation to plasma volumes measured using 125I-labeled albumin (7, 8, 52). M-mode echocardiography was used to measure left ventricular end-systolic and end-diastolic diameters from the apical long-axis view. Two-dimensional echocardiography and continuous-wave Doppler (Biosound Esaote, Indianapolis, IN) were used to determine aortic cross-sectional area (parasternal long-axis view at the point of cusp insertion) and flow (systolic velocity integral), respectively. Aortic flow, arterial pressure, and central venous pressure were monitored for 1 min while the subject breathed to a metronome to minimize variations in central venous pressure. The stabilization period and the entire protocol, except measurement of plasma volume and {alpha}2- and {beta}2-adrenoreceptor densities and affinities, were repeated at –10° tilt (an angle at which cardiopulmonary and arterial baroreceptors would be relatively loaded compared with the supine position), 20° tilt (an angle at which cardiopulmonary baroreceptors are relatively unloaded compared with the supine position), and 30° tilt (an angle at which cardiopulmonary and arterial baroreceptors are relatively unloaded compared with the supine position) (20, 42, 57). Finally, orthostatic tolerance was evaluated with a 30-min, 70° tilt. Only hemodynamic measurements were collected during 70° tilt. A subject was characterized as presyncopal during the 70° tilt if 1) systolic pressure fell to <70 mmHg, 2) systolic pressure fell >25 mmHg, 3) diastolic pressure fell >15 mmHg, and 4) heart rate dropped >15 beats/min. Data were recorded on digital tape and videotape for later analyses.

Head-down bed rest. Subjects were confined to 12 days of strict bed rest and monitored 24 h/day. Subjects were allowed to turn in the bed, support their head with only one pillow, and rise on one elbow to eat, urinate, or defecate.

On day 12 of bed rest, plasma volume was measured. On day 13 of bed rest, subjects followed the standard fluid-loading procedure used by the astronauts on landing day, i.e., within a 2-h period, oral consumption of one 1.0-g salt tablet per 125 ml of water, with a total volume of 15 ml/kg body wt. Subjects were weighed and then transferred from their bed to the tilt table via a stretcher to repeat the pre-bed-rest measurements.

Analyses. The following parameters were calculated from measurements described above: stroke volume (systolic velocity integral x aortic cross-sectional area), cardiac output (heart rate x stroke volume), vascular resistance (mean arterial pressure ÷ cardiac output), left ventricular volume {7/[(2.4 + left ventricular diameter)(left ventricular diameter)3]}, and ejection fraction [(left ventricular end-diastolic volume – left ventricular end-systolic volume) ÷ left ventricular end-diastolic volume]. Stroke volumes and cardiac outputs each were divided by the subject’s body surface area [0.007184 x (weight in kg)0.425 x (height in cm)0.725] to create an indexed parameter used for statistical analysis. For discussion purposes, all nonindexed terms were used.

Radioenzymatic assays were used to analyze plasma catecholamines (56) and angiotensin I (Biotex Laboratories, Friendswood, TX). Plasma renin activity was estimated from the production of angiotensin I (46). Plasma aldosterone (50) and arginine vasopressin (26) were quantified by radioimmunoassay. Platelet {alpha}2- and lymphocyte {beta}2-adrenoreceptor densities and affinities were determined as described by DeBlasi et al. (14) and Motulsky et al. (36), respectively.

Table 1 indicates the sample size for each parameter, inasmuch as we were unable to analyze all parameters in all subjects. Particularly, central venous pressure and echocardiographic data at –10° tilt were not usable. It appeared that the central catheter tip was blocked in that position, possibly because of a cephalic shift of the heart.


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  		Table 1. Sample sizes of hemodynamic and endocrine variables at each level of tilt

 
Statistics. Values are means ± SE. Data were tested for normalcy and equal variance using the Kolmogorov-Smirnov test and the Levene median test, respectively. All variables were compared before and after bed rest (day 13). In addition, blood, plasma, and red blood cell volumes measured on day 12 were compared with values before bed rest and on day 13 using one-tailed paired t-tests. In addition, 90% confidence intervals for the mean change (over bed rest) in blood, plasma, and red blood cell volumes were calculated. Differences in hemodynamic and endocrine variables before and after bed rest were analyzed using a one-way (day as main effect) or two-way (day and tilt angle as main effects) repeated-measures ANOVA, and Tukey’s post hoc test was performed to document differences in variables when there was a significant main effect. For all tests, significance was set at P ≤ 0.05.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Restoration of plasma volume. Mean plasma, blood, and red blood cell volumes are shown in Table 2. In 9 of the 10 subjects, day 0 and day 12 data were collected; the losses in plasma, blood, and red blood cell volumes were 8%, 5%, and 0.9%, respectively. Subjects’ weights did not change significantly as a result of bed rest: 72.3 ± 2.9 and 70.7 ± 2.8 kg before and after bed rest, respectively (P = 0.81).


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  		Table 2. Plasma, blood, and red blood cell volumes on days 0, 12, and 13 of bed rest

 
Hemodynamic and hormonal responses. None of the 10 subjects became presyncopal during 70° upright tilt after bed rest. However, before bed rest, one subject asked to be returned to the supine position during minute 27 of 70° tilt, although his arterial pressure was not within the limits set to define presyncope in this study.

The results of the two-way repeated-measures ANOVA are shown in Table 3. Figure 1 depicts hemodynamic variables at all levels of tilt. In the supine position, no hemodynamic variable changed as a result of bed rest. In the tilted positions, heart rate was the only hemodynamic variable that was significantly affected by bed rest; responses to tilt were augmented. Figure 2 depicts central venous pressures, left ventricular end-systolic and end-diastolic diameters, and ejection fractions. Only central venous pressure showed a significant effect of bed rest (day x tilt angle effect, P < 0.03), inasmuch as central venous pressure fell less from supine to 20° tilt than before bed rest but fell to the same level at 30° tilt. Figure 3 presents plasma arginine vasopressin, renin activity, aldosterone, norepinephrine, and epinephrine levels. Only renin activity and epinephrine showed day effects (P < 0.05 and P < 0.001, respectively). Increases in renin activity and epinephrine in response to tilt were augmented after bed rest. Figure 4 shows the aldosterone-to-renin ratio at each angle of tilt before and after bed rest (day effect, P < 0.05). The ratio was significantly reduced after bed rest only in the supine position (P = 0.05); however, there was a trend for the ratio to be reduced at –10° and 20° tilt (P = 0.08 and P = 0.07, respectively).


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  		Table 3. Results of two-way repeated-measures ANOVA

 


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  		Fig. 1. Arterial pressure, heart rate (beats/min, bpm), stroke index, cardiac index, and vascular resistance responses to –10°, 0°, 20°, 30°, and 70° tilt in healthy men before and after bed rest. Values are means ± SE. *P < 0.01 vs. pre-bed rest.

 


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  		Fig. 2. Central venous pressure, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and ejection fraction responses to 0°, 20°, and 30° tilt in healthy men before and after bed rest. Values are means ± SE.

 


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  		Fig. 3. Plasma arginine vasopressin, renin activity, aldosterone, norepinephrine, and epinephrine responses to –10°, 0°, 20°, and 30° tilt in healthy men before and after bed rest. Values are means ± SE. *P < 0.05; ** P < 0.01 vs. pre-bed-rest.

 


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  		Fig. 4. Ratio of plasma aldosterone to plasma renin activity at –10°, 0°, 20°, and 30° tilt in healthy men before and after bed rest. Ratio was calculated after units for plasma renin activity were converted to pg·ml–1·h–1. Values are means ± SE. *P = 0.05 vs. post-bed-rest.

 
Adrenoreceptor responses. Figure 5 depicts the densities and affinities of platelet {alpha}2- and lymphocyte {beta}2-adrenoreceptors. The {beta}2-adrenoreceptor density was increased after bed rest (P = 0.05). There were no changes in density of {alpha}2-adrenoreceptors or affinities of {alpha}2- or {beta}2-adrenoreceptors.



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  		Fig. 5. Density and affinity of {alpha}2-adrenoreceptors and {beta}2-adrenoreceptors in healthy men before and after bed rest. Values are means ± SE. Kd, dissociation constant. *P = 0.05, pre- vs. post-bed-rest.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This is the first head-down bed-rest study of which we are aware that included an oral fluid load equivalent to that given to astronauts before Shuttle landings, before data were collected at the end of bed rest. This protocol more closely models the spaceflight experience and separates this bed-rest study from all others. There are three important findings from this study. 1) No subject in this study experienced orthostatic hypotension at the end of bed rest. This differs substantially from the incidence of orthostatic hypotension (weighted average of 49%) reported from other studies (Table 4). 2) Supine hemodynamic and endocrine variables did not change after bed rest. 3) Despite the normovolemia after bed rest, {beta}2-adrenoreceptors were upregulated, and heart rate, epinephrine, and plasma renin responses to tilt were augmented; these changes represent primary effects of bed rest. Collectively, these findings offer insight regarding separation of primary effects of bed rest from secondary effects caused by hypovolemia.


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  		Table 4. Effects of strict –6° head-down bed rest variables collected at rest and in response to orthostatic stress

 
Orthostatic hypotension. We report that oral fluid loading after bed rest restored plasma volume and resulted in 0% presyncope. Our finding contrasts with those of other bed-rest studies that have tested orthostatic tolerance (Table 4), none of which employed fluid-restoring countermeasures (2, 9, 21, 23, 28, 34, 38, 39, 48, 49). Our findings also contrast with the results of Vernikos and Convertino (53), who conducted the only other known study in subjects who consumed an oral fluid load before measurements were collected at the end of bed rest. Four of their five subjects became presyncopal with fluid loading after bed rest. However, their fluid-loading protocol did not restore plasma volume. The only apparent difference between the two regimens was the total volume administered. In our regimen (which restored plasma volume), the total volume of the fluid load was based on the body weight of each subject; in the other regimen (which did not restore plasma volume), the total volume was predetermined (960 ml). If this predetermined volume had been used in our subjects, instead of volume determined on the basis of weight, 8 of the 10 subjects would have received a lower total volume of the fluid load. Our finding that elimination of the plasma volume loss reduced the incidence of orthostatic hypotension is supported by the study of Vernikos and Convertino, which also tested the efficacy of a plasma volume expander, fludrocortisone, to reduce volume losses after bed rest. Fludrocortisone reduced post-bed-rest plasma volume losses to within 4% of pre-bed-rest values and substantially reduced the incidence of orthostatic hypotension to 16%. To our knowledge, the study of Vernikos and Convertino is the only other study to attempt plasma volume restoration of subjects at the end of bed rest. We suggest that the restoration of plasma volume with salt tablets and water (15 ml/kg) in our study was the factor that reduced post-bed-rest orthostatic hypotension in our subjects.

In our subjects, 1 liter of an isotonic solution (salt tablets and water) restored ~250 ml of the lost plasma volume, but the distribution of remaining fluid load is not known. One possibility is that the remaining fluid moved into the extracellular spaces. We did not measure extracellular fluid volume in this study; thus we cannot be certain that there was a total rehydration of the subjects with the fluid load. This loss may be of functional importance in some, but not all, individuals. In a previous study, we showed that presyncopal and nonpresyncopal male astronauts have virtually identical plasma volume losses on landing day (~250 ml) (55). Nonpresyncopal astronauts compensate for this loss with increased activation of the sympathetic nervous system during tilt. Presyncopal astronauts do not mount this response. Thus a plasma volume loss of 250 ml can be problematic to them.

Efficacy of fluid loading: bed rest vs. spaceflight. In this study, we used the same fluid-loading protocol that is used by astronauts on the day of reentry. Use of this protocol on day 13 of bed rest restored plasma volume in all our subjects from an average 8% loss on day 12. This fluid-loading protocol, however, does not have the same effect in astronauts returning from space. We and others have reported that, despite the use of the same fluid load, astronauts return from space with plasma volume decrements of 5–19% (6, 16, 27, 32, 55). One possible explanation for this discrepancy is that plasma volume losses after spaceflight may be greater than those after bed rest. However, even if one assumes that the magnitude of the volume loss is the same during spaceflight and during bed rest, other factors come into play after spaceflight that may further reduce the volume loss. Many astronauts suffer from neurovestibular disturbances that cause nausea and vomiting during reentry and after landing. This could exacerbate volume depletion for the returning astronauts and interfere with fluid loading itself. Bed-rest subjects rarely experience such symptoms.

Orthostatic hypotension and presyncope, in response to stand or tilt tests, occur in ~30% of astronauts returning from short-duration missions (6, 16, 32, 55). No astronaut that we have studied has returned from space volume replete compared with preflight (16, 31, 32, 55). Therefore, it has not been possible to know whether volume repletion would improve postspaceflight orthostatic hypotension. However, we have reported identical plasma volume losses in presyncopal and nonpresyncopal male astronauts after flight (55). In the same study, we reported that female astronauts, whose incidence of presyncope is significantly higher than that of the men, have greater postspaceflight plasma volume losses than the men, suggesting that the relative contribution of plasma volume loss to orthostatic hypotension may vary depending on gender (55). We also showed that other factors, such as autonomic dysfunction, probably play a more important role in postspaceflight orthostatic hypotension than plasma volume loss (16, 31, 32, 55). On the basis of our previous findings in astronauts, the results from the present study must be interpreted carefully. The fact that restoration of plasma volume resulted in a zero rate of presyncope in bed-rested men does not necessarily suggest the same outcome in bed-rested women or in astronauts after flight. Additional measures most likely are needed for women and astronauts.

Effects of bed rest that are independent of plasma volume. In our subjects, plasma volume was restored before the collection of measurements at the end of bed-rest; thus any changes from pre-bed-rest to post-bed-rest would not have occurred secondarily to plasma volume losses. The only hemodynamic effect of bed rest in the present study was increased heart rate responses to 20°, 30°, and 70° tilt. We offer two possible explanations for this finding. First, head-down bed rest may reduce the tonic inhibitory influence of cardiopulmonary baroreceptor input on the arterial baroreflex control of heart rate (37), resulting in decreased cardiac vagal and/or increased cardiac sympathetic efferent activity, either of which could result in an increased heart rate during upright tilt. Bed rest has been shown to reduce cardiac vagal, but not cardiac, sympathetic efferent activity during orthostatic stress (13). This supports the idea that only the cardiac vagal outflow is disrupted.

A second explanation for the increase in heart rate responses is the increase in cardiac {beta}2-adrenergic receptors, which mediate large chronotropic effects (5, 19, 29). The evidence for this is inferential. We found a greater density of {beta}2-adrenergic receptors on lymphocytes after bed rest. This may reflect a similar change in cardiac {beta}2-adrenergic receptors (3, 4, 33). The idea of increased cardiac {beta}2-adrenergic receptor function after bed rest is supported by studies that have shown increased lymphocyte {beta}2-adrenergic receptors (30) and increased heart rate responses to epinephrine infusions after bed rest (1). Upregulation of {beta}-adrenergic receptors could have occurred in response to sympathoinhibition. Several reports indicate that norepinephrine release is attenuated during bed rest (10–12). Although plasma norepinephrine levels during bed rest were not measured in the present study, supine norepinephrine values (collected ~20 min after transition from head-down bed rest) tended to be reduced after bed rest and may reflect sympathoinhibition during bed rest.

The explanation for the increases in epinephrine and renin responses to tilt is not clearly defined in this study. The augmented epinephrine release may simply reflect a heightened acute stress response to tilt as a result of the chronic stress of bed rest (17, 40). The enhanced renin response has been shown previously (but without restoration of plasma volume), although no explanation was offered (34, 54).

Our study shows a dissociation of the independent effects of head-down bed rest on control of adrenoreceptors, epinephrine, and renin activity. Although we cannot be sure that our subjects were fully rehydrated after bed rest, arterial pressure and plasma volume appear to contribute more importantly to the regulation of the sympathetic nervous system and the renin-angiotensin system than does extracellular fluid volume (43–45). There could be several possible explanations for the dissociation. 1) Increased sympathetic outflow certainly could increase renin responses to head-up tilt, but if this were the case, it would be expected that plasma norepinephrine responses also would have been augmented in our subjects. No report has demonstrated an enhanced sympathetic response to orthostatic stress after bed rest (23, 34, 48). 2) The central integration of baroreceptor input may be affected, resulting in an uncoupling of the normal response. This idea is supported by data from hindlimb-suspended rats, an animal model of microgravity, which showed changes in the central processing of baroreceptor input (35). 3) An increase in {beta}-adrenoreceptor density or sensitivity, with or without a concomitant increase in sympathetic outflow, could enhance release of renin. In addition to {beta}1-adrenoreceptors, {beta}2-adrenoreceptors also have been implicated in renin release (15, 51). Our present findings and those of others (1, 12, 30) show evidence for increased {beta}-adrenoreceptor density and/or sensitivity after bed rest, with and without plasma volume restoration, respectively. We know of no study that has reported a decrease in {beta}-adrenoreceptor responsiveness after bed rest.

We also noted that the aldosterone-to-renin ratio was reduced after bed rest. This finding agrees with other bed-rest studies (34, 54). In one of those studies, concomitant measures of ACTH, angiotensin II, and electrolytes were collected but did not exhibit any changes that could account for the uncoupling (54). In our subjects, the ratio was lower after than before bed rest at –10°, 0°, and 20° tilt but was virtually identical at 30° tilt (when cardiopulmonary baroreceptors are completely unloaded), again suggesting a disruption of the cardiopulmonary-arterial baroreceptor reflex interaction.

The possibility that these changes could occur in response to the acute fluid load should be addressed. Only two supine variables changed after bed rest: {beta}2-adrenergic receptor density increased, and the ratio of aldosterone to plasma renin activity decreased. Identical changes after bed rest have been reported in subjects who had not consumed an acute fluid load (30, 34, 54). This observation, along with the fact that no other supine variable changed after bed rest, supports the idea that the acute fluid load itself was not responsible for the changes we observed after bed rest. The changes we observed appear to be primary effects of bed rest.

Effects of bed rest that are secondary to plasma volume losses. With the exception of the heart rate responses to tilt, no other hemodynamic variable (supine or in response to tilt) changed after 12 days of bed rest in our normovolemic subjects. This contrasts with findings reported in hypovolemic, bed-rested subjects and suggests that bed-rest-induced changes in supine hemodynamic variables occur secondarily to the loss of plasma volume. This idea also is supported by data from Iwasaki et al. (21), who used a diuretic to reduce plasma volume by 11% and reproduced the bed-rest-induced increases in heart rate and decreases in plasma volume, stroke volume, right atrial pressure, and pulmonary capillary wedge pressure.

The supine values of the hormones also had not changed as a result of bed rest, although there was a trend for reduced norepinephrine release. This suggests that, similar to the hemodynamic variables, bed-rest-induced changes in supine endocrine variables may occur primarily in response to the hypovolemia.

Limitations. All subjects initially enrolled did not complete the study. These subjects could not be replaced; thus the remaining, smaller sample size could have introduced more type II beta error than originally designed.

In the present study, all subjects were given a standard hospital diet; yet strict intake of electrolytes was not measured. Alterations in sodium and potassium intake could affect hormones of the renin-angiotensin system; however, because a relatively high amount of sodium was provided, we would expect plasma renin activity to be low. We noted no change in supine values, and responses to tilt were augmented, rather than suppressed.

Although the plasma volume loss reported in this study was not statistically significant (P = 0.06), it is likely to be of functional importance. The loss of plasma volume in this bed-rest study is comparable to that reported for male astronauts after spaceflight (55).

To most accurately determine loss of total volume and subsequent rehydration, fluid balances of intake and output should be documented. In this study, these measurements unfortunately were not collected. Thus we cannot be certain whether the total extracellular fluid volume was replaced with the fluid load.

Conclusions. The findings of the present study offer new insight regarding primary hemodynamic and endocrine effects of bed rest. Restoration of plasma volume in subjects before the end-of-study measurements after bed rest resulted in a zero rate of orthostatic hypotension and presyncope, an absence of change in resting hemodynamic and endocrine variables from before bed rest, and an upregulation of {beta}2-adrenoreceptors. The changes in the heart rate, epinephrine, and plasma renin responses to tilt after bed rest represent primary effects of bed rest that are independent of hypovolemia and may reflect 1) a heightened acute stress response, 2) a disruption in the central integration of baroreceptor input, and/or 3) an enhancement of {beta}-adrenergic sympathetic responsiveness.

Perspectives

Our findings have direct relevance to the development of countermeasures for postspaceflight dehydration and orthostatic hypotension. The fluid-loading regimen used in this bed-rest study was identical to that used by astronauts before reentry. This regimen resulted in correction of plasma volume loss and a zero rate of presyncope during tilt testing in bed-rested subjects but results in a 7–19% plasma volume loss and a 30% rate of presyncope during tilt testing on landing day in our subjects. As mentioned above, it may prove impossible to restore plasma volume before reentry. Therefore, this laboratory has chosen to pursue and develop countermeasures that can help support arterial pressure in the presence of the fluid loss. We have targeted midodrine, an {alpha}1-adrenergic agonist that prevents orthostatic hypotension in bed-rested subjects in whom plasma volume has not been restored. Flight studies are underway to pursue this finding (41).

With respect to the present study, no subject became presyncopal during tilt testing after bed rest; {beta}2-adrenoreceptors were upregulated; and heart rate, plasma renin, and epinephrine responses to tilt were augmented. If we extrapolate the augmented epinephrine and plasma renin responses at low-level tilt to 70° tilt, we may expect that those responses would be augmented as well. An increased epinephrine and plasma renin response may be necessary to prevent presyncope after bed rest. We propose that an individual unable to elicit these responses may succumb more readily to presyncope, certainly in the setting of hypovolemia.


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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
This research was supported by National Aeronautics and Space Administration Grant NCC9-105.


   ACKNOWLEDGMENTS
 
We thank the subjects who participated in the study. We thank the personnel of National Aeronautics and Space Administration-Johnson Space Center’s Cardiovascular Laboratory for assistance with data collection and analysis and Dr. Alan Feiveson for assistance with statistical analysis.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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