mise à jour du
5 février 2006
Am J Physiol Heart Circ Physiol
2002; 282; 6; H2210-15
Attenuated sympathetic nerve responses
after 24 hours of bed rest
Khan MH, Kunselman AR, Leuenberger UA, Davidson WR Jr, Ray CA, Gray KS, Hogeman CS, Sinoway LI.
Division of Cardiology, Pennsylvania State University College of Medicine, Milton S Hershey Medical Center, Hershey,USA.


Abstract : Bed rest reduces orthostatic tolerance. Despite decades of study, the cause of this phenomenon remains unclear. In this report we examined hemodynamic and sympathetic nerve responses to graded lower body negative pressure (LBNP) before and after 24 h of bed rest. LBNP allows for baroreceptor disengagement in a graded fashion. We measured heart rate (HR), cardiac output (HR x stroke volume obtained by echo Doppler), and muscle sympathetic nerve activity (MSNA) during a progressive and graded LBNP paradigm. Negative pressure was increased by 10 mmHg every 3 min until presyncope or completion of -60 mmHg. After bed rest, LBNP tolerance was reduced in 11 of 13 subjects (P <.023), HR was greater (P <.002), cardiac output was unchanged, and the ability to augment MSNA at high levels of LBNP was reduced (rate of rise for 30- to 60-mmHg LBNP before bed rest 0.073 bursts x min(-1) x mmHg(-1); after bed rest 0.035 bursts x min(-1) x mmHg(-1); P < 0.OI6). These findings suggest that 24 h of bed rest reduces sympathetic nerve responses to LBNP.
When normal human subjects rise to the standing position, gravitational forces lead to pooling of blood in dependent areas. This leads to a reduction in venous return. The normal physiological responses to this stress are increases in heart rate (HR) and peripheral vascular resistance. These reflex responses act to maintain blood pressure and preserve cerebral and cardiac perfusion. When these responses are impaired, the threshold for orthostatic intolerance (OI) decreases.
Bed rest and spaceflight reduce the threshold for OI. Despite decades of study, debate continues as to whether this OI is primarily due to an inability to maintain cardiac output (CO) or to a reduced ability to raise peripheral vascular resistance.
In this study, we performed 24-h bed rest experiments to examine this issue. We selected 24 h of bed rest because it is sufficient to impair orthostatic tolerance (OT) yet leads to a relatively small reduction in plasma volume and heart muscle mass compared with changes seen with longer bed rest paradigms. Significant changes in plasma volume have been shown to contribute to OI. Therefore, we hypothesized that if muscle sympathetic nerve activity (MSNA) responses were impaired after 24 h of bed rest it would strongly point to "peripheral" causes of OI.
During the lower body negative pressure (LBNP) tests we measured HR and blood pressure, made peripheral sympathetic nerve recordings, and calculated stroke volume (SV), peripheral vascular resistance, and cardiac output. The results of these experiments demonstrate that bed rest reduces tolerance to graded LBNP. This effect was associated with a reduced ability to increase MSNA at higher levels of LBNP.
The most common symptoms during LBNP at the end of the study before and after bed rest were lightheadedness and dizziness followed by yawning, nausea, feeling of warmth, and abdominal discomfort.
LBNP tolerance. Before bed rest five subjects completed the entire paradigm, whereas after bed rest only two did so. Before bed rest the LBNP test was stopped because of hypotension in seven subjects and because of nausea in one subject. After bed rest the test was discontinued because of hypotension in nine subjects, because of nausea in one subject, and because of cold sweats in one subject. The modified cumulative stress index was lower after bed rest (P < 0.023), with 11 of the 13 subjects being less tolerant to the paradigm after bed rest.
Cardiovascular responses. The cardiovascular responses to LBNP before and after bed rest are shown as a change from baseline ∆ in Fig. 2. The number of subjects at each level of LBNP for each variable is shown in Table 1. During the LBNP paradigm, ZHR rose to a greater degree after bed rest (bed rest effect P < 0.0OI8). After bed rest ASV values were generally lower than the values noted at the same level of LBNP before bed rest, but no statistical effect of bed rest was noted. CO, the product of HR and SV, fell with LBNP but was unaffected by bed rest (not significant). LSVR and mean arterial pressure (MAP) with LBNP were also unaffected by bed rest. Because we used the blood pressure values at the earliest signs of LBNP intolerance, we did not observe a lower BP at the highest level of tolerable LBNP after bed rest.
To examine the effects of bed rest on MSNA, the rate of change measured as z bursts and z bursts/100 heartbeats was calculated for "low levels" (baseline to -30mmHg) and "high levels" (-30 mmllg to end LBNP) of LBNP. This analysis demonstrated that the rate of increase in MSNA at low levels of LBNP was similar before and after bed rest. However, the rate of increase in MSNA for high levels of LBNP was lower after bed rest (Fig. 3). This was noted despite the fact that MAP values tended to be lower. MSNA values before and after LBNP are shown in Table 2.
The main findings of this study were that 1) after bed rest subjects were less tolerant of LBNP than before, 2) the ∆CO response to LBNP was not altered by bed rest, and 3) the rate of increase of LMSNA during high levels of LBNP was lower after bed rest than before. This latter effect was seen despite the fact that absolute blood pressure at each level of LBNP tended to be lower after bed rest than before. This suggests that the reduced MSNA response to LBNP after bed rest was not due to a smaller hypotensive stimulus. Thus 24 h of bed rest is a sufficient stimulus to alter the MSNA-∆ blood pressure stimulus-response relationship.
The potential causes for this decline in orthostatic tolerance after bed rest (or spaceflight) can be grouped into those that may accentuate the fall in CO and those that lead to an impairment in the vasoconstrictor response seen with orthostatic stress. It is clear that bed rest or spaceflight leads to reductions in plasma volume, which can reduce ventricular filling and in the process lead to an accentuated reduction in CO with standing. However, the incidence of OI after headdown bed rest (HDBR) or spaceflight is not well correlated with reductions in plasma volume, and restoring plasma volume (and central venous pressure) to before bed rest levels does not restore OT. In the present report we limited the period of bed rest to 24 h because this time period does not allow the full expression of the fall in plasma volume seen with bed rest.
Several investigators have suggested that increased lower limb venous compliance after bed rest or spaceflight may contribute to OI. However, orthostatic hypotension has been observed within 4 h of head-down tilt, before any changes in peripheral venous compliance could occur.
Work by Levine et al. suggested that the inability of volume replacement to normalize OT may be due to cardiac atrophy. We doubt that cardiac atrophy contributed to the OI observed in the present study because LBNP intolerance was observed after only 24 h of bed rest. The main stimulus for cardiac protein synthesis is the rate-pressure product. We are not aware of any data to suggest that the ratepressure product falls after bed rest. Moreover, even if it did decline, it is doubtful that 24 h of a reduced rate-pressure product would be sufficient stimulus to reduce protein synthesis and cause cardiac atrophy, and therefore this response is not likely to explain the present findings.
The autonomic regulatory systems controlling blood pressure responses to postural stress include the cardiopulmonary, aortic, and carotid baroreflexes and yestibular inputs. Hypotension evokes an increase in efferent sympathetic vasoconstrictor activity as well as parasympathetic withdrawal that leads to an increase in HR. With HDBR, the sensitivities of the arterial and cardiopulmonary baroreflexes appear to be reduced. Furthermore, the greatest reduction in barorefiex gain is found in subjects demonstrating the greatest OI after bed rest. This impairment appears to be specific for the vasoconstrictor arm of this reflex because HR responses are not impaired. The mechanism for the reduced ability to raise sympathetic nerve activity after immobilization is unclear. Recent work by Moffitt et al. in a rat model suggests that the baroreflex impairment after hindlimb unweighting is due to altered central processing of baroreceptor input.
Recently, it was suggested that myogenic responses are impaired after bed rest. Reduced myogenic responses could contribute to impaired vasoconstriction with postural stress seen after bed rest. However, this would not explain the reduced MSNA responses after bed rest. Nevertheless, the present report does not allow us to exclude an effect of bed rest on myogenic activity.
As mentioned above, 24 h of bed rest does not lead to large changes in plasma volume and/or cardiac atrophy. Therefore, the results of the present study may not explain OI seen after longer periods of bed rest.
In this study, subjects underwent a graded LBNP paradigm until presyncope or -60 mmHg level. Thus presyncope was not observed in 5 of 13 subjects before and 2 of 13 subjects after bed rest. This limits our ability to precisely quantify the magnitude of OT in this study. Nonetheless, 11 of 13 subjects had a reduction in the cumulative LBNP index used. Thus we believe our contention that LBNP tolerance was reduced after HDBR is valid.
In conclusion, after 24 h of bed rest, LBNP tolerance was reduced, HR was greater, CO was unchanged, and the ability to augment MSNA at high levels of LBNP was reduced. These findings suggest that 24 h of bed rest is sufficient to interfere with the ability to raise MSNA normally with LBNP.