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EXPERIMENT INFORMATION

Gender Differences in Bedrest: Autonomic and Neuroendocrine Changes and Vascular Responses in Lower and Upper Extremities (BEDREST0543)

Description
OBJECTIVES:
Female astronauts are more susceptible to orthostatic hypotension and presyncope after space flight than are male astronauts. However, most space flight and bed rest studies that have sought to understand the mechanisms contributing to this increased incidence of orthostatic hypotension have not included women. Consequently, many conclusions about the effects of microgravity or simulated microgravity on humans are seriously flawed in that they fail to describe mechanisms in the very people who have the most serious problems.

Before flight, low vascular resistance in female astronauts is not associated with lower sympathetic responsiveness, as their supine and standing norepinephrine levels are similar to those of men. This suggests that the gender differences may lie in the responsiveness of the vasculature itself. Premenopausal women appear to have greater endothelium-dependent venodilatory as well as vasodilatory responses than those of men. This suggests that their lower resistance and lower venous return may be nitric oxide-mediated. Many studies have documented hemodynamic changes that occur during and after space flight or bed rest; very few have examined directly vascular responses, fewer still have compared vascular responses in men versus women before and after bed rest, and none has examined both arteries and veins. Therefore, the first purpose of this study was to examine vascular responsiveness in arteries and veins, in women versus men, before and after bed rest.

Important new information emerged in the animal literature that shows that different vascular beds respond differently to simulated microgravity. After male rats are hindlimb-suspended, vessels in their forelimbs undergo hypertrophic remodeling while vessels in their hindlimbs undergo atrophic remodeling. This is thought to occur as a result of the differential changes in transmural pressures and wall shear stress in the fore- and hindlimbs during the suspension. These studies have not been repeated in female rats. Upright humans have more than a 140 mmHg pressure gradient from head to foot. Elimination of this gradient would change the mechanical forces acting on the vasculature in the legs to an even greater extent than in the suspended rats. It is likely that humans in bed rest or space flight would show similar differential regional changes. Since humans are bipedal, both space flight and bed rest would greatly reduce pressures and wall shear stress in the vessels in the legs, but not the arms. Thus atrophic changes would be expected in the vasculature of the legs but not of the arms. This idea has not been pursued in humans, but such changes certainly could contribute to orthostatic hypotension. Therefore, the second purpose of this study was to compare changes in vascular responsiveness in the upper and lower extremities before and after bed rest and relate the findings to the occurrence of orthostatic hypotension.

Female astronauts, as well as a small subset of male astronauts, develop autonomic dysfunction during space flight. In these astronauts, sympathetic responsiveness to orthostatic stress is compromised after flight. Furthermore, both bed rest and space flight studies have shown decreased vagal activity and baroreflex sensitivity, yet these studies have primarily examined male subjects. Therefore, the third purpose of this study was to compare both autonomic and endocrine responses to arterial baroreceptor input in men and women before and after bed rest.

Specific Aim 1:
Compare arterial function in men and women before and after bed rest. It was hypothesized that woman, compared to men, would have greater flow-mediated vasodilation in the brachial and anterior tibial artery and that this gender difference would be exaggerated after bed rest. It was also hypothesized that brachial and anterior tibial artery vasodilation in response to sublingual nitroglycerin will not be different between women and men.

Specific Aim 2:
Compare venous function in men and women before and after bed rest. It was hypothesized that dorsal hand and foot veins of women would dilate more in response to acetylcholine; and constrict more in response to L-NMMA than men, and leg compliance will be greater in women. These gender differences will be exaggerated after bed rest.

Specific Aim 3:
Compare responses in the lower extremity before and after bed rest. Investigators tested the hypothesis that, after bed rest: anterior tibial artery diameter increases will be smaller following ischemia and larger following sublingual nitroglycerin; dorsal foot vein responses to phenylephrine, isoproterenol, acetylcholine and L-NMMA will be smaller after bed rest, and leg compliance will be greater after bed rest.

Specific Aim 4:
Compare responses in the upper extremity before and after bed rest. Investigators tested the hypothesis that, after bed rest: brachial artery diameter increases will be greater following ischemia and smaller following sublingual nitroglycerin; and that dorsal hand vein responses to phenylephrine, isoproterenol, acetylcholine and L-NMMA will be increased after bed rest.

Specific Aim 5:
Tested the hypothesis that women will have a greater loss of neuroendocrine responses to arterial baroreceptor input after bed rest than men.
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Publications
Arzeno NM, Stenger MB, Lee SMC, Ploutz-Snyder R, and Platts SH. Gender differences in blood pressure control during 6-degree head-down tilt bed rest. American Journal of Physiology: Heart Circulatory Physiology. 2013. April; 304(8):H1114-23. [pubmed.gov]

Westby CM, Martin DS, Lee SM, Stenger MB, and Platts SH. Left ventricular remodeling during and after 60 days of sedentary head-down bed rest. Journal of Applied Physiology (1985). 2016. April 15; 120(8):956-64. pubmed.gov

Keywords
Hyperemia
Vascular resistance
Hypotension, orthostatic
Presyncope

Data Information
Data Availability
Archive is complete. Data sets are not publicly available but can be requested.
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Parameters
Acetylcholine Infusion
Calcium
Calf venous compliance
Cortisol
Creatinine
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Mission/Study Information
Mission Launch/Start Date Landing/End Date Duration
Campaign 3 02/20/2005 04/14/2010 5 years, 1 month, 25 days

Human Research Program (HRP) Human Research Roadmap (HRR) Information
Crew health and performance is critical to successful human exploration beyond low Earth orbit. The Human Research Program (HRP) investigates and mitigates the highest risks to human health and performance, providing essential countermeasures and technologies for human space exploration. Risks include physiological and performance effects from hazards such as radiation, altered gravity, and hostile environments, as well as unique challenges in medical support, human factors, and behavioral health support. The HRP utilizes an Integrated Research Plan (IRP) to identify the approach and research activities planned to address these risks, which are assigned to specific Elements within the program. The Human Research Roadmap is the web-based tool for communicating the IRP content.

The Human Research Roadmap is located at: https://humanresearchroadmap.nasa.gov/

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Additional Information
Managing NASA Center
Johnson Space Center (JSC)
Responsible NASA Representative
Johnson Space Center LSDA Office
Project Manager: Pamela A. Bieri
Institutional Support
National Aeronautics and Space Administration (NASA)
Alternate Experiment Name
BRC04-JSC03
Proposal Source
BRC-2003-0000-0543