Space-flight and its ground-based simulation model, 6° head-down bed rest (HDBR), cause cardiovascular deconditioning in humans. Because sympathetic vasoconstriction plays a very important role in circulation, we examined whether HDBR impairs α-adrenergic vascular responsiveness to sympathetic nerve activity. We subjected eight healthy volunteers to 14 days of HDBR and before and after HDBR measured calf muscle sympathetic nerve activity (MSNA; microneurography) and calf blood flow (venous occlusion plethysmography) during sympathoexcitatory stimulation (rhythmic handgrip exercise). HDBR did not change the increase in total MSNA (P = 0.97) or the decrease in calf vascular conductance (P = 0.32) during exercise, but it did augment the increase in calf vascular resistance (P = 0.0011). HDBR augmented the transduction gain from total MSNA into calf vascular resistance, assessed as the least squares linear regression slope of vascular resistance on total MSNA (0.05 ± 0.02 before HDBR, 0.20 ± 0.06 U·min-1·burst-1 after HDBR, P = 0.0075), but did not change the transduction gain into calf vascular conductance (P = 0.41). Our data indicate that α-adrenergic vascular responsiveness to sympathetic nerve activity is preserved in the supine position after HDBR in humans.
- vascular contractility
exposure to microgravity, as in spaceflight, causes cardiovascular deconditioning in humans (1, 3, 22, 37, 38). Deconditioning is also produced in humans by a ground-based simulation model of microgravity, 6° head-down bed rest (HDBR) (2, 12, 18-20). The most characteristic problem of this deconditioning is orthostatic intolerance (1, 12, 22, 37). Although sympathetic vasoconstriction plays a very important role in circulation (30), it remains unclear whether exposure to actual and simulated microgravity impairs α-adrenergic vascular responsiveness to sympathetic nerve activity. Several animal and human studies have addressed this issue but failed to provide a definitive answer. Studies in rats showed that hindlimb unloading (a simulation of microgravity in rats) reduced vascular contractile responses to cumulatively added neurotransmitter (norepinephrine) in isolated arteries (4-7, 29, 41). In contrast, an earlier study in humans (2) showed that 14 days of HDBR did not affect the dose-dependent increase in calf vascular resistance during intravenous infusion of phenylephrine, an α-receptor agonist. Unfortunately, however, the vascular response reported was no doubt affected by baroreflex compensation. To our knowledge, the vascular response to intra-arterial infusion of phenylephrine after HDBR was presented only in one preliminary study by Pawelczyk and Levine (25) in abstract form. They suggested that HDBR had little consequence to vascular sensitivity to direct α-adrenergic vasoconstrictive stimuli. However, pharmacological vascular contraction induced by the infusion of phenylephrine is different from the physiological sympathetic vascular contraction that includes neurotransmitter (norepinephrine) kinetics, which can be altered (blunted) after microgravity.
In the present study, we tested the hypothesis that HDBR impairs α-adrenergic vascular responsiveness to sympathetic nerve activity in humans. We subjected eight healthy volunteers to a 14-day period of HDBR, and before and after HDBR we investigated calf vascular responsiveness (resistance and conductance) to calf muscle sympathetic nerve activity (MSNA) during sympathoexcitatory stimulation (rhythmic handgrip exercise). Following the procedure of an earlier study (15), we determined the transduction gain of sympathetic nerve activity into vascular resistance and conductance by using least squares linear regression.
This study involved eight male subjects, with a mean age of 23 ± 3 (SE) yr, mean height of 170 ± 3 cm, and mean weight of 66 ± 3 kg. All subjects were evaluated as healthy from a detailed medical history, physical examination, complete blood count, resting electrocardiogram, panel of blood chemistry analyses, and psychological test. No subjects smoked, used recreational drugs, or had chronic medical problems. All experimental procedures and protocols were approved by the Ethical Committee of the National Space Development Agency of Japan (NASDA). All subjects provided voluntary, informed consent to all procedures and risks.
HDBR. For 14 days, subjects adhered strictly to the requirements of HDBR, maintaining a 6° head-down position. During HDBR, staff nurses continuously monitored subjects to ensure that they remained head down without interruption and without physical exercise. Dietary intake was set at 2,100 to 2,300 kcal/day (55% carbohydrate, 25% fat, 20% protein). Fluid intake from daily drinks was ad libitum and averaged 1,281 ± 68 ml/day. The photoperiod was 16 h of light and 8 h of darkness, with lights on at 0700. Caffeinated beverages were strictly prohibited throughout the course of the experiment.
Handgrip exercise. As in an earlier study (15), we used handgrip exercise to assess the transduction of MSNA into calf vascular responsiveness during sympathoexcitatory stimulation. Handgrip exercise evokes a highly reproducible pressor response mediated by progressive and parallel increases in calf MSNA and calf vascular resistance (15, 31). This assessment was used as a nonpharmacological method of quantifying the transduction process (15).
We instructed the subjects to refrain from exercise and food intake for 3 h before beginning HDBR. Subjects lay supine on a bed in an air-conditioned room with a temperature of 26-27°C and a humidity of 40%. First, each subject performed two brief (<5 s) maximal contractions with the dominant arm to determine his maximal voluntary contraction by using a handgrip dynamometer (Digital Grip Dynamometer, Takei Kiki Kogyo). We defined the average of these two contractions as the maximal voluntary contraction force.
Second, at least 1 h after determination of maximal force, we made a preexercise baseline recording of MSNA (right leg), calf blood flow (left leg), finger blood pressure (nondominant forearm), heart rate, and respiratory rate for 10 min while subjects remained supine on the bed. Finally, 12 min of rhythmic handgrip exercise was performed with the dominant arm at 30% of the maximal voluntary contraction force. The handgrip exercise consisted of 2 s of contraction and 2 s of rest. Subjects were required to breathe at the rate of 15 breaths/min (2 s of expiration and 2 s of inspiration) guided by a speaker on a personal computer. Subjects were required neither to breathe deeply nor to do Valsalva maneuvers. They were required not to contract other limbs. The absolute force output from a handgrip dynamometer was displayed to the subjects on an oscilloscope, together with the target force. All variables were monitored during each exercise. In addition, blood samples to determine plasma catecholamine concentrations were obtained from the antecubital vein of the nondominant forearm during preexercise rest and 2 min after the end of exercise.
After HDBR, we measured the maximal voluntary handgrip force. Then, we conducted rhythmic handgrip exercise in a similar manner as before HDBR. Because HDBR is known not to affect the maximal handgrip force, we used similar absolute contraction intensities of handgrip exercise before and after HDBR.
Stand test. Because the most characteristic problem of the cardiovascular deconditioning after HDBR is orthostatic intolerance, we performed a stand test to assess the relationship between occurrence of orthostatic intolerance after HDBR and possible alteration in vascular responsiveness to MSNA. After at least 30 min of rest in the horizontally supine position after handgrip exercise, we conducted 15 min of active stand testing. We terminated the stand testing when any of the following were observed: the development of presyncopal symptoms, such as nausea, sweating, yawning, pallor, or dizziness; a drop in systolic blood pressure of >20 mmHg that was sustained over 10 consecutive heartbeats; or a progressive reduction in systolic blood pressure to <80 mmHg.
Finger blood pressure was continuously measured with a pneumatic finger cuff (Portapres, TNO Institute of Applied Physics Biomedical Instrumentation) (39). Portapres finger cuffs were noninvasively attached to two digits of the nondominant arm, and each was inflated alternately to prevent pain due to continuous air pressure load. Also continuously monitored were the electrocardiogram, from chest lead II, and respiration, by a thermistor. Mean blood pressure was calculated as diastolic blood pressure plus one-third of pulse pressure. The indexes of cardiac output and stroke volume were determined by computation from finger blood pressure by using a nonlinear, three-element model described by Wesseling et al. (39).
MSNA was continuously measured as reported elsewhere (35). Briefly, a tungsten microelectrode (model 26-05-1, Federick Haer and Bowdoinham) was inserted percutaneously into the muscle nerve fascicles of the tibial nerve at the right popliteal fossa without anesthesia. Nerve signals were fed into a preamplifier (Kohno Instruments, Nagoya, Japan) with two active band-pass filters set between 500 and 5,000 Hz and were monitored with a loudspeaker. MSNA was identified according to the following discharge characteristics: 1) pulse synchronous spontaneous efferent discharges, 2) afferent activity being induced by tapping of calf muscles but not in response to gentle skin touch, and 3) enhancement during phase II of the Valsalva maneuver. The MSNA signal was stored on a DAT recorder (PC216Ax, Sony Magnescale) at a sampling rate of 12,000 Hz, along with other cardiovascular variables. The MSNA signal was full-wave rectified, fed through a low-pass filter with a time constant of 0.1 s to obtain the mean voltage neurogram, and then resampled at 1,000 Hz along with other cardiovascular variables. We identified MSNA bursts and calculated the burst areas with a computer. MSNA was evaluated as MSNA burst rate, i.e., the mean number of sympathetic bursts per minute, and total MSNA, i.e., a summation of the MSNA burst amplitudes of all bursts during each analyzed period. To calculate the MSNA burst amplitude in the mean voltage neurogram, all burst amplitudes were measured by using a digitizing tablet. The mean value per minute of total MSNA (the sum of all MSNA burst amplitudes) during 10 min of preexercise rest was given the arbitrary value of 100 sympathetic activity units per minute, and total MSNA during exercise was expressed relative to this value.
Calf blood flow was measured by using venous occlusion and mercury-in-Silastic strain-gauge plethysmography (16) on the left leg. While the subject was supine, the calf was placed 10-15 cm above the right atrium to collapse the veins. Occlusion cuffs were placed around the thigh just above the knee and around the ankle. Care was taken to place the strain gauge in the same place in the pre- and post-HDBR trials. An arterial occlusion cuff around the ankle was continuously inflated to 250 mmHg to arrest circulation to the foot, while a venous occlusion cuff around the thigh was inflated to 50 mmHg for 7 s every 15 s, providing one calf blood flow measurement every 15 s. Calf vascular resistance was calculated by dividing mean blood pressure by calf blood flow and expressed as peripheral resistance units. Calf vascular conductance was calculated by dividing calf blood flow by mean blood pressure and expressed as peripheral conductance units.
Plasma norepinephrine concentrations were also measured. Blood samples were taken during preexercise rest and 2 min after the end of contraction, as in an earlier study (10) that showed that the peak of plasma norepinephrine concentration occurred 2 min after the cessation of a handgrip exercise similar to that in this study. After centrifugation, plasma was divided into multiple aliquots and frozen at -80°C until analysis. The norepinephrine concentrations were obtained via electrochemical detection after high-performance liquid chromatography over alumina, as previously described (8). The sensitivity for norepinephrine analysis was 1 pg/ml. The within- and between-assay coefficients of variability were 3 and 6%, respectively.
Transduction of Sympathetic Activity into Vascular Resistance and Conductance
In each trial, values of MSNA, calf vascular resistance, conductance, and other variables were averaged for 10-min preexercise baseline periods, and then every 3 min during 12 min of handgrip exercise. This exercise is known to increase MSNA and vascular resistance while decreasing vascular conductance. We calculated the least squares linear regression slope of calf vascular resistance and conductance on MSNA and defined the transduction of MSNA into vascular resistance (15) and conductance, respectively. In all trials, we obtained a significant (P < 0.05) positive correlation coefficient (>0.7) between calf vascular resistance and MSNA, and a negative correlation coefficient (>0.7) between calf vascular conductance and MSNA. We calculated these transduction gains in all trials.
Data are expressed as means ± SE. The effects of the HDBR on variables were evaluated by a two-way repeated-measures analysis of variance [condition (before vs. after HDBR) and protocol time]. When the main effect or interaction term was found to be significant, post hoc comparisons were made with the Sheffé's F procedure. The effects of HDBR on the slopes and intercepts of transduction regressions were evaluated by a paired Student's t-test.
Preexercise Baseline Measurements
HDBR increased baseline MSNA burst rate (P = 0.08; Fig. 1). It did not change heart rate (P = 0.85) and mean blood pressure (P = 0.80; Table 1). It reduced calf blood flow (P = 0.0006; Table 1), increased calf vascular resistance (P = 0.0004; Fig. 1), and decreased calf vascular conductance (P = 0.0010; Fig. 2). It decreased indexes of cardiac output (P = 0.0012) and stroke volume (P = 0.0004; Table 1).
Sympathetic and Cardiovascular Response to Exercise
The maximal voluntary contraction force was similar before (457 ± 23 N) and after (454 ± 28 N) HDBR (P = 0.84). Before and after HDBR, rhythmic handgrip exercise elicited progressive increases in MSNA burst rate (F = 11.5, P = 0.0001), total MSNA (F = 14.4, P = 0.0001; Fig. 1), and calf vascular resistance (F = 19.6, P = 0.0001; Fig. 1), whereas it produced a progressive decrease in calf vascular conductance (F = 10.8, P = 0.0001; Fig. 2). HDBR did not change the increases in MSNA burst rate (F = 1.19, P = 0.33) and total MSNA (F = 0.13, P = 0.97) during exercise (Fig. 1). In contrast, HDBR augmented the increase in calf vascular resistance during exercise (F = 5.30, P = 0.0011; Fig. 1). HDBR did not change the decrease in calf vascular conductance during exercise (F = 1.21, P = 0.32; Fig. 2). HDBR did not affect the responses of heart rate (F = 0.94, P = 0.45), mean blood pressure (F = 0.68, P = 0.61), calf blood flow (F = 0.81, P = 0.52), and respiratory rate (F = 0.03, P = 0.99) during exercise (Table 1). HDBR reduced the indexes of cardiac output (F = 8.3, P = 0.012) and stroke volume (F = 17.5, P = 0.0009) during exercise.
Transduction of Sympathetic Nerve Activity into Vascular Responsiveness
There was a significant positive correlation between MSNA and calf vascular resistance during baseline rest and exercise, shown by a high r value. HDBR increased the transduction gain from MSNA to vascular resistance assessed as the least squares linear regression slope of vascular resistance on MSNA (Fig. 1) in each expression of MSNA in burst rate (P = 0.045) and total activity (P = 0.0075). The intercept of the regression was similar before and after HDBR.
There was a significant negative correlation between MSNA and calf vascular conductance during baseline rest and exercise, yielding a high r value. The HDBR did not change the transduction gain from MSNA to vascular conductance assessed as the least squares linear regression slope of vascular conductance on MSNA (Fig. 2), neither in expression of MSNA in burst rate (P = 0.75) nor in total activity (P = 0.41). The intercept of the regression was similar before and after HDBR.
Plasma Norepinephrine Response to Exercise
Before and after HDBR, handgrip exercise increased plasma norepinephrine concentration (F = 51.3, P = 0.001). HDBR augmented the increase in rhythmic exercise by 57%, from 77 ± 24 pg/ml before HDBR to 122 ± 14 pg/ml after HDBR (F = 10.2, P = 0.01; Table 2).
Before HDBR, all eight subjects completed 15 min of stand testing without any signs or symptoms of orthostatic hypotension. After HDBR, four of the eight subjects experienced orthostatic hypotension, with symptoms of presyncope that warranted termination of the stand test. The duration of the test to termination was 3.4, 7.7, 9.3, and 12.5 min in these subjects.
Regardless of the occurrence of post-HDBR orthostatic hypotension, HDBR increased the transduction from MSNA into vascular resistance in all subjects, although it did not change that into conductance (Figs. 1 and 2). The HDBR similarly augmented the exercise-induced increase in plasma norepinephrine concentration in subjects with and without post-HDBR orthostatic hypotension.
Exposure to spaceflight and its ground-based simulation model, HDBR, causes cardiovascular deconditioning in humans (1, 2, 12, 13, 18, 19, 22, 37, 38, 40). Although sympathetic vasoconstriction plays a very important role in circulation (30), it remains unclear whether the cardiovascular deconditioning includes an impairment of α-adrenergic vascular responsiveness to sympathetic nerve activity. The major new finding of the present study is that the 14-day HDBR augmented the transduction gain from MSNA into calf vascular resistance during sympathoexcitatory stimulation (handgrip exercise), whereas it did not affect the transduction gain from MSNA into calf vascular conductance. The present result does not support our above-mentioned hypothesis and indicates that α-adrenergic vascular responsiveness to sympathetic nerve activity is preserved in the supine position after HDBR in humans.
Although we found different effects of HDBR on transduction from MSNA into vascular resistance (increased after HDBR) and conductance (unchanged after HDBR), both findings may point to the same conclusion: α-adrenergic vascular responsiveness to sympathetic nerve activity appears intact after HDBR. Regarding vascular resistance vs. conductance as an index of vasomotor responses, O'Leary (24) provided the following important observations. The effect of a given change in resistance on arterial pressure may be strongly dependent on the baseline level of resistance. In contrast, the same change in regional conductance always causes the same change in arterial pressure, regardless of the initial value of conductance. Therefore, O'Leary concluded that changes in conductance far better reflect the importance of the response in pressure regulation than do changes in regional resistance. Indeed, in the present study, HDBR increased baseline calf vascular resistance but decreased baseline calf vascular conductance. Therefore, our finding of unchanged transduction gain with conductance rather than increased gain with resistance could reflect a true effect of HDBR on vascular responsiveness. However, we should apply his finding to our experiment carefully, since we focused on vascular responsiveness to sympathetic nerve activity, whereas O'Leary was examining the arterial pressure response to resistance and conductance. We thus investigated the transduction gain by using both resistance and conductance. Because HDBR reduced neither the gain with resistance nor the conductance, HDBR did not impair α-adrenergic vascular responsiveness to MSNA.
Our data suggest that HDBR may alter neurotransmitter (norepinephrine) kinetics, because HDBR did not change increases in MSNA during exercise but increased plasma norepinephrine concentration by 159%. This finding is consistent with the recent study from the Neurolab space shuttle mission showing that spaceflight did not change the upright tilt-induced increase in MSNA (although level of MSNA burst rate was elevated) but augmented the increase in plasma norepinephrine concentration from 125 pg/ml before to 304 pg/ml after spaceflight (22). Because in the Neurolab study no returning astronaut suffered from orthostatic hypotension during upright posture on Earth, it might be possible that plasma norepinephrine concentration was only elevated in subjects who remain orthostatically tolerant. However, this is unlikely, because HDBR augmented the exercise-induced increase in plasma norepinephrine even in subjects who suffered from post-HDBR orthostatic hypotension. In addition, the study from the Neurolab space shuttle mission indicated that, in space, norepinephrine spillover was augmented more than norepinephrine reuptake, with the result that plasma norepinephrine was increased (9).
Although HDBR augmented the increase in vascular resistance during handgrip exercise, this was likely counteracted by lower cardiac output. Consequently, the increase in blood pressure during handgrip exercise was unchanged by HDBR.
There are several mechanisms that may be responsible for augmented transduction of sympathetic nerve activity into vascular resistance after HDBR. The first possibility is the wall-tolumen arteriolar relation (11). Smooth muscle wall thickening means that any contraction will reduce the radius more than it would have if wall thickening were not present. In the present study, resting vascular resistance was greater after HDBR. Therefore, the same MSNA and the same α-adrenergic receptor properties would be expected to provoke a greater reduction in the lumen.
The second possible mechanism is increased α-adrenergic sensitivity of the vascular contractile response to released neurotransmitter (norepinephrine). Although an earlier study (2) showed that HDBR did not affect the increase in calf vascular resistance in response to intravenous infusion of phenylephrine, the vascular response reported was no doubt affected by baroreflex compensation and thus could have been underestimated. This possibility may not be consistent with a preliminary study by Pawelczyk and Levine (25), which suggested that HDBR has little effect on the sensitivity of calf vascular resistance in response to intra-arterial infusion of phenylephrine. However, because the study is presented only in abstract form, the detail of data is unknown.
Although we found that α-adrenergic vascular responsiveness to sympathetic nerve activity is preserved after HDBR in humans, the finding was inconsistent with earlier in vitro studies in rodents (4, 5, 7, 29, 41). These studies showed that, in rats, 2-3 wk of hindlimb unloading (a simulation model of microgravity in rats) induced reductions of vascular contractile response to cumulatively added norepinephrine concentrations (10-9 to ∼10-4 M) in isolated thoracic and abdominal aorta, carotid, mesenteric, and femoral arteries and skeletal muscle arterioles (4, 5, 7, 29, 41). These attenuated responses could be caused by a decrease in myofibrillar proteins and smooth muscle atrophy (6). The discrepancy may, we think, be due to differences in species (humans vs. rodents) and experimental design (in vivo vs. in vitro experiments). Changes in norepinephrine clearance with HDBR could be a factor in our study but not in the earlier in vitro studies. Moreover, even if HDBR attenuated vascular contractile response to α-adrenergic stimuli in humans, this could be overridden by higher norepinephrine concentrations after HDBR (as suggested by our finding that the exercise-induced increase in norepinephrine was higher after HDBR, whereas that in MSNA was unchanged).
The present finding appears to conflict with one earlier study in humans (33), which showed that HDBR slightly blunted the ability of the cold pressor test (vasoconstrictor stimulus) to decrease reactive hyperemic blood flow in the forearm. However, that study addressed a complex physiological condition that involved vasodilator (circulatory arrest) and vasoconstrictor (cold pressor test) stimuli, not a pure α-adrenergic vascular response to sympathetic nerve activity. Moreover, although it investigated forearm hemodynamics, the α-adrenergic sensitivity of vascular responsiveness has been reported to be different in the calf and forearm (26). The sensitivity is greater in the calf than in the forearm, probably in connection with an adaptive mechanism related to orthostatic gravitational stress (26). Therefore, the data from the forearm in the earlier HDBR study cannot simply be applied to the vascular characteristics in the leg that we investigated in the present study.
Because we obtained the present data from subjects in the horizontally supine position, we cannot extrapolate to the hemodynamic condition during standing. It is because, in the supine human, intraluminal arterial pressure in the leg arterial vasculature would be ∼100 mmHg, whereas when upright it would be 180-200 mmHg (30), a tremendously large load for resistance artery vasoconstriction. Therefore, we are limited by our data to discussing the pathophysiology of orthostatic hypotension after HDBR. Similar limitations were present in previous investigations of vascular responsiveness to adrenergic stimulation after HDBR (2, 25).
Although our present findings appear to conflict with pioneering studies from spaceflight by Buckey et al. (1) and Fritsh-Yelle et al. (13), their studies have a problem. They reported that total vascular resistance and plasma norepinephrine concentration during stand testing after spaceflight was lower in astronauts with postflight orthostatic hypotension than those without (1, 13), suggesting that postflight orthostatic hypotension might be partly due to blunted sympathetic vasoconstriction. This suggestion was confirmed by a recent study addressing gender differences in postflight orthostatic hypotension (38). In addition, we have also showed that vasoconstrictor sympathetic nerve activity is decreased at the last pressurefalling stage of orthostatic hypotension after HDBR (20), similar to some orthostatic neurally mediated syncopes in patients and healthy subjects without HDBR (23). The problem with their pioneering studies from spaceflight is the subjects' position when blood samples were taken. In the study of Fritsh-Yelle et al. (13), blood was taken for norepinephrine determination in the supine position in presyncopal astronauts but in the upright position in nonpresyncopal astronauts. The difference in position could account for the lower plasma norepinephrine concentration observed in presyncopal astronauts.
Our present finding that HDBR did not affect the increase in MSNA during rhythmic handgrip exercise may be consistent with four recent studies from the Neurolab space shuttle mission (3, 9, 14, 22). These studies have demonstrated completely normal increases in MSNA, norepinephrine spillover, systemic vascular resistance, and blood pressure control during lower body negative pressure (9), the Valsalva maneuver (3), head-up tilt (22), and both handgrip and cold pressor tests (14). The normal sympathetic function was consistent with a study involving HDBR (27) that showed an unchanged relation between MSNA and cardiac filling pressure. Our data indicate that sympathetic response to forearm exercise is intact after HDBR, regardless of the occurrence of post-HDBR orthostatic hypotension.
The present study has several limitations that could modify plasma norepinephrine concentration factors and their relationship with MSNA. First, reduction of plasma volume after HDBR (12, 37) could reduce norepinephrine clearance and lead to overestimates of plasma norepinephrine concentration. However, this seems unlikely because a recent study (9) has showed an increase in norpinephrine clearance after spaceflight that could provide an underestimation, rather than an overestimation, of norepinephrine concentration after microgravity.
Second, the plasma norepinephrine concentration determined from the forearm vein reflects neurotransmitter spillover from a number of vascular sites (34, 36), whereas MSNA specifically estimates sympathetic outflow in leg skeletal muscle (35). Thus, if increases in sympathetic outflows to some vascular areas during exercise were augmented after HDBR, it would explain the augmented exercise-induced increase in plasma norepinephrine concentration after HDBR, despite similar MSNA activation, as we observed in the present study. Unfortunately, sympathetic outflows to vascular areas other than leg skeletal muscle were not measured in this study. However, we believe that these limitations do not influence the relationship between MSNA and calf vascular resistance.
Finally, although leg MSNA has been considered a primary cause of the increase in calf vascular resistance (15, 31), a contribution from a pressure-sensitive myogenic vasoconstrictive mechanism in skeletal muscle has also been described (21, 28). This possibility seems to be supported by an earlier study in humans (32) showing a very transient difference between MSNA and femoral artery vascular resistance (calculated from vascular flow measured by Doppler ultrasound) at the onset of postexercise muscle ischemia after handgrip exercise. Moreover, another earlier study in humans (17) reported that the increase in vascular resistance (calculated from vascular flow measured by Doppler ultrasound) in response to upright tilt was greater in the leg than in the arm and the increase in MSNA was similar. That study suggested an interaction between α-receptor-mediated vasoconstriction and pressure-sensitive myogenic response, particularly in the leg when in an upright position. In contrast with these earlier studies, in the present study, we investigated the nearly steady-state (not transient) sympathetic and cardiovascular condition in the horizontally supine (not upright) position. Therefore, although we cannot exclude a possible contribution of pressure-sensitive myogenic vasoconstriction, we believe that sympathetic activity is a major direct mechanism for an increase in calf vascular resistance in the supine position.
In conclusion, our data showed that 14-day HDBR augmented the transduction gain from MSNA into calf vascular resistance during sympathoexcitatory stimulation (handgrip exercise), whereas it did not affect the transduction gain from MSNA into calf vascular conductance. These data indicate that α-adrenergic vascular responsiveness to sympathetic nerve activity is completely intact after HDBR in humans who are in the supine position.
This study was supported in part by a Grant-in-Aid for Scientific Research (no. 13770032) from the Ministry of Education, Science, Sport, and Culture of Japan.
This study was carried out as a part of “Ground Research Announcement for Space Utilization” promoted by the Japan Space Forum.
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.
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