Human exploration of space: why, where, what for?

"Man must rise above Earth to the top of the atmosphere and beyond, for only then will he fully understand the world in which he lives"-Socrates (469-399 BC). The basic driving rationales for human space flight (HSF) are rooted in age-old and persisting dreams. Fascination with the idea of people going into the sky for adventures in other worlds goes back to ancient myths. This paper sheds light onto criticisms of HSF programs, by revisiting their scientific grounds and associated benefits, along with the different types of emerging commercial enterprise. Research from space has lead to a wealth of commercial and societal applications on Earth, building up the case for the so-called "Space Applications Market".

The therapeutic benefits of gravity in space and on earth.

The traditional scientific approach of investigating the role of a variable on a living organism is to remove it or the ability of the organism to sense it. Gravity is no exception. Access to space has made it possible for us to begin the exploration of how gravity has influenced our evolution, our genetic make-up and our physiology. Identifying the thresholds at which each body system perceives, how much, how often, how long the gravity stimulus is needed and in which direction should it be presented for maximum effectiveness, is fundamental knowledge required for using artificial gravity as a therapeutic or maintenance countermeasure treatment in exploration missions. Here on earth, although surrounded by gravity we are negligent in using gravity as it was intended, to maintain the level of health that is appropriate to living in 1G. These, changes in lifestyle or pathologies caused by various types of injury can benefit as well from artificial gravity in much the same way as we are now considering for astronauts in space.

From space to Earth: advances in human physiology from 20 years of bed rest studies (1986-2006).

Bed rest studies of the past 20 years are reviewed. Head-down bed rest (HDBR) has proved its usefulness as a reliable simulation model for the most physiological effects of spaceflight. As well as continuing to search for better understanding of the physiological changes induced, these studies focused mostly on identifying effective countermeasures with encouraging but limited success. HDBR is characterised by immobilization, inactivity, confinement and elimination of Gz gravitational stimuli, such as posture change and direction, which affect body sensors and responses. These induce upward fluid shift, unloading the body's upright weight, absence of work against gravity, reduced energy requirements and reduction in overall sensory stimulation. The upward fluid shift by acting on central volume receptors induces a 10-15% reduction in plasma volume which leads to a now well-documented set of cardiovascular changes including changes in cardiac performance and baroreflex sensitivity that are identical to those in space. Calcium excretion is increased from the beginning of bed rest leading to a sustained negative calcium balance. Calcium absorption is reduced. Body weight, muscle mass, muscle strength is reduced, as is the resistance of muscle to insulin. Bone density, stiffness of bones of the lower limbs and spinal cord and bone architecture are altered. Circadian rhythms may shift and are dampened. Ways to improve the process of evaluating countermeasures--exercise (aerobic, resistive, vibration), nutritional and pharmacological--are proposed. Artificial gravity requires systematic evaluation. This review points to clinical applications of BR research revealing the crucial role of gravity to health.

Blood pressure changes during orthostatic stress: evidence of gender differences in neuroeffector distribution.

BACKGROUND: Research has demonstrated that exogenous adrenergic agonists produce dose-related vasoconstriction in men but not women. This suggests that the distribution of adrenergic receptor sites differ with gender. Women may have a higher density of receptor sites in the arterioles (fast acting with low gain) while men may have higher density in the larger vessels (slow acting with high gain). METHODS: To partially test this hypothesis, the time course in beat-to-beat responses in systolic and diastolic BP, and heart rate was compared between six men and six women during the transition from a supine to an upright posture and during prolonged standing. RESULTS: The transient change in systolic and diastolic BP was very rapid in women, but completed within 15 to 30 s after assuming an upright position. Men increased BP at a much slower rate, but continued to produce higher BPs over the complete testing session (up to 15 min). The rate of change for men (15 mm Hg systolic and 10 mm Hg diastolic) was approximately half that for women (30 mm Hg systolic and 15 mm Hg diastolic) during the first 30 s of upright posture. However, after 60 s of standing, absolute change in systolic BP for the men exceeded that of the women by approximately 5 mm Hg for both systolic and diastolic BP. While men's heart rate remained relatively constant during standing, women compensated for the lower change in BP by a continual increase in heart rate throughout the duration of the test. Although both men and women demonstrated increases in norepinephrine at 5 and 15 min during standing, no difference between genders was observed. Similarly, there were no differences in dominant periodicity of heart rate during standing, although women demonstrated slightly higher beat-to-beat variation (RMS) than men. CONCLUSION: The results support the hypothesis of distributional differences in neuroeffector responses between men and women and have implications for how men and women respond to orthostatic stress across a variety of environmental conditions.

Dietary salt and urinary calcium excretion in a human bed rest spaceflight model.

BACKGROUND: Dietary salt is known to increase the excretion of urinary calcium (Ca). To determine the potential role of dietary sodium (Na) on the calciuria associated with a spaceflight simulation model, we evaluated urinary Ca in two groups of bed rest subjects fed either high or low normal amounts of salt. METHODS: We analyzed urinary Ca excretion expressed in terms of creatinine (UCa/Cr), fractional Ca excretion (FECa), and urinary cAMP (UCAMP) as an index of parathyroid function, in the urine of 30-50-yr-old male volunteers for 6 degrees head down tilt bed rest studies. Dietary Na was in the high normal range (190 mmol x d(-1)) in 8 men for 7 d (HiNa), and in the low normal range (114 mmol x d(-1)) in 11 men for 30 d (LoNa) bed rest. Dietary Ca averaged 20 mmol x d(-1) in both studies. RESULTS: Within the first 3 bed rest days, subjects in the HiNa study showed increases in UCa/Cr (0.1130 +/- 0.05 to 0.161 +/- 0.05, p < 0.002) and in FECa (1.95 +/- 0.70 to 3.19 +/- 0.93, p < 0.001); those in LoNa showed no change in UCa/Cr (0.125 +/- 0.06 to 0.121 +/- 0.07, NS) or FECa (1.93 +/- 0.75 to 2.22 +/- 0.63). After the 5th bed rest day UCa/Cr stabilized at similar levels in both dietary groups. UCAMP decreased 20% during the first week of bed rest with HiNa, but not until the third week with LoNa diets (p < 0.05). CONCLUSION: These findings implicate high salt diets in Ca excretion in a spaceflight model and suggest that low normal salt diets may reduce early calciuria associated with spaceflight.

Physiological changes in spaceflight that may affect drug action.

Despite nearly 40 years of spaceflight, the paucity of time spent in microgravity and somewhat scattered approach to the study to pharmacology in microgravity have resulted in little solid information. Moreover, they have generally only been studied in the first few days of spaceflight or its simulation by bedrest, when physiological changes are most dynamic. Nevertheless, early physiological responses to microgravity have been well documented and provide good support for the hypothesis that both pharmacokinetics and pharmacodynamics should be altered, with more significant changes occurring as stays in space increase in duration. Whether given orally, by intravenous (IV) or intramuscular (IM) injection, intranasally (IN) or rectally, a drug must distribute through the body, usually crossing certain membranes and becoming bound to other molecules, reach its receptor and bind to it in order to exert its action. This paper, then, will follow a drug's passage through the body in terms of pharmacokinetic parameters known to be affected by microgravity, and mention other factors.

Effects of exposure to simulated microgravity on neuronal catecholamine release and blood pressure responses to norepinephrine and angiotensin.

We tested the hypothesis that exposure to microgravity reduces the neuronal release of catecholamines and blood pressure responses to norepinephrine and angiotensin. Eight men underwent 30 days of 6 degrees head-down tilt (HDT) bedrest to simulate exposure to microgravity. Plasma norepinephrine and mean arterial blood pressure (MAP) were measured before and after a cold pressor test (CPT) and graded norepinephrine infusion (8, 16 and 32 ng/kg/min) on day 6 of a baseline control period (C6) and on days 14 and 27 of HDT. MAP and plasma angiotensin II (Ang-II) were measured during graded Ang-II infusion (1, 2 and 4 ng/kg/min) on C8 and days 16 and 29 of HDT. Baseline total circulating norepinephrine was reduced from 1017ng during the baseline control period to 610 ng at day 14 and 673ng at day 27 of HDT, confirming a hypoadrenergic state. An elevation of norepinephrine (+178 ng) to the CPT during the baseline control period was eliminated by HDT days 14 and 27. During norepinephrine infusion, similar elevations in plasma norepinephrine (7.7 pg/ml/ng/kg/min) caused similar elevations in MAP (0.12 mmHg/ng/kg/min) across all test days. Ang-II infusion produced higher levels of plasma Ang-II during HDT (47.3 pg/ml) than during baseline control (35.5 pg/ml), while producing similar corresponding elevations in blood pressure. While vascular responsiveness to norepinephrine appears unaffected, impaired neuronal release of norepinephrine and reduced vascular responsiveness to Ang-II might contribute to the lessened capacity to vasoconstrict after spaceflight. The time course of alterations indicates effects that occur within two weeks of exposure.

The International Space Life Sciences Working Group.

The International Space Life Sciences Working Group (ISLSWG) is made up of representatives from five space agencies: the National Aeronautics and Space Administration (NASA), the European Space Agency (ESA), the Canadian Space Agency (CSA), the Centre National d'Etudes Spatiale (CNES), the Deutsches Zentrum fur Luft- und Raumfahrt (DLR, formerly the Deutsche Agentur fur Raumfahrtangelegenheiten or DARA), and the National Space Development Agency of Japan (NASDA). The group met for the first time in 1989, and since that time has developed a Strategic Plan and has taken concrete steps to implement this plan. The result is a closely coordinated international program of Space Life Sciences which will enable optimal utilization of space flight opportunities.

Artificial gravity intermittent centrifugation as a space flight countermeasure.

NASA: Head-down bed rest was used to simulate weightlessness in an experiment that examined variations in dose, time, and frequency of +Gz stimuli countermeasures. Results indicate that 4 hr. standing was most effective for orthostatic intolerance, walking was most effective in achieving peak oxygen consumption, 4 hr. of standing or walking had the best effect on plasma volume, and 4 hr. of walking was most effective in maintaining urinary calcium excretion.^ieng

Human physiology in space.

The universality of gravity (1 g) in our daily lives makes it difficult to appreciate its importance in morphology and physiology. Bone and muscle support systems were created, cellular pumps developed, neurons organised and receptors and transducers of gravitational force to biologically relevant signals evolved under 1g gravity. Spaceflight provides the only microgravity environment where systematic experimentation can expand our basic understanding of gravitational physiology and perhaps provide new insights into normal physiology and disease processes. These include the surprising extent of our body's dependence on perceptual information, and understanding the effect and importance of forces generated within the body's weightbearing structures such as muscle and bones. Beyond this exciting prospect is the importance of this work towards opening the solar system for human exploration. Although both appear promising, we are only just beginning to taste what lies ahead.

Effect of standing or walking on physiological changes induced by head down bed rest: implications for spaceflight.

BACKGROUND/HYPOTHESIS: To simulate exposure to microgravity and to determine the effectiveness of intermittent exposure to passive and active +1 Gz force (head-to-foot) in preventing head-down bed rest (HDBR) deconditioning, 4 d of 6 degrees HDBR were used. METHODS: Volunteers were 9 males, 30-50 yr, who performed periodic standing or controlled walking for 2 or 4 h.d-1 in 15-min bouts, one bout per hour, or remained in a continuous HDBR control condition (0 Gz). RESULTS: Standing 4 h (S4) completely prevented, and standing 2 h (S2) partially prevented, decreases in post-HDBR orthostatic tolerance (survival rates with 30 min of upright tilt at 60 degrees). Walking, both 2 h (W2) and 4 h (W4), and S4 attenuated decreases in peak oxygen uptake compared to 0 Gz. Compared to 0 Gz, both S4 and W4 attenuated plasma volume loss during HDBR. Urinary Ca2+ excretion increased over time with HDBR; the quadratic trend for urinary Ca2+, however, was attenuated with W2 and W4. CONCLUSIONS: We concluded that various physiological systems benefit differentially from passive +1 Gz or activity in +1 Gz and, in addition to the duration of the stimulus, the number of exposures to postural stimuli may be an important moderating factor.

Catecholaminergic effects of prolonged head-down bed rest.

Prolonged head-down bed rest (HDBR) provides a model for examining responses to chronic weightlessness in humans. Eight healthy volunteers underwent HDBR for 2 wk. Antecubital venous blood was sampled for plasma levels of catechols [norepinephrine (NE), epinephrine, dopamine, dihydroxyphenylalanine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid] after supine rest on a control (C) day and after 4 h and 7 and 14 days of HDBR. Urine was collected after 2 h of supine rest during day C, 2 h before HDBR, and during the intervals 1-4, 4-24, 144-168 (day 7), and 312-336 h (day 14) of HDBR. All subjects had decreased plasma and blood volumes (mean 16%), atriopeptin levels (31%), and peripheral venous pressure (26%) after HDBR. NE excretion on day 14 of HDBR was decreased by 35% from that on day C, without further trends as HDBR continued, whereas plasma levels were only variably and nonsignificantly decreased. Excretion rates of dihydroxyphenylglycol and dihydroxyphenylalanine decreased slightly during HDBR; excretion rates of epinephrine, dopamine, and dihydroxyphenylacetic acid and plasma levels of catechols were unchanged. The results suggest that HDBR produces sustained inhibition of sympathoneural release, turnover, and synthesis of NE without affecting adrenomedullary secretion or renal dopamine production. Concurrent hypovolemia probably interferes with detection of sympathoinhibition by plasma levels of NE and other catechols in this setting. Sympathoinhibition, despite decreased blood volume, may help to explain orthostatic intolerance in astronauts returning from spaceflights.

Introduction.

NASA: The introduction to a special issue on weightlessness countermeasures provides a brief overview of weightlessness countermeasures and examines the physiology of spaceflight, which includes short- and long-term effects of weightlessness and physiological adaptation.^ieng

Pharmacological approaches.

NASA: The use of drugs as countermeasures in the United States and Russian space programs is examined. Pharmacological tools for short and extended space flights are reviewed. Medications flown on the Shuttle are listed. Considerations for the use of pharmacological countermeasures include pharmacokinetics and pharmacodynamics, drug interactions, therapeutic interventions, space motion sickness, the musculoskeletal system, radiation protection, space flight anemia, and cardiovascular disorders.^ieng

A sensitive radioimmunoassay for fludrocortisone in human plasma.

Fludrocortisone has been a mainstay of therapy for orthostatic hypotension for many years. Clinical experience suggests that there exists a substantial interindividual variation in responsiveness to the drug. To assess this, we have developed an assay that permits measurement of the low concentrations of fludrocortisone found in human plasma. Fludrocortisone was detected by radioimmunoassay. A polyclonal rabbit antibody, raised against dexamethasone which cross-reacts strongly with fludrocortisone, was reacted with either standard or unknown samples in the presence of [125I]fludrocortisone-3-TyrNH2 (synthesized by coupling tyrosine amide to fludrocortisone-3-oxime and iodinating with chloramine T oxidation). The ED10, ED50, and ED80 were 0.34, 5.0, and 30 ng/mL of plasma, respectively. The cross reactivity with other 9-fluorinated steroids was found as follows: dexamethasone, 340%; betamethasone, 230%; and triamicinolone, 8%. To preclude an erroneous result, subjects who were pregnant or receiving any steroid medication were excluded from the study. The percent cross-reactivity with the main naturally occurring steroids was as follows: 11-desoxycortisol 3.2%, cortisol 1.1%, DOC 0.3%, pregnenolone 0.1%, corticosterone 0.06%, progesterone 0.05%, and aldosterone < 0.05%. The only compound with potential for interference, because of its high level in the circulation in the early morning, was cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)

The sympathetic nervous system and the physiologic consequences of spaceflight: a hypothesis.

Many of the physiologic consequences of weightlessness and the cardiovascular abnormalities on return from space could be due, at least in part, to alterations in the regulation of the autonomic nervous system. In this article, the authors review the rationale and evidence for an autonomic mediation of diverse changes that occur with spaceflight, including the anemia and hypovolemia of weightlessness and the tachycardia and orthostatic intolerance on return from space. This hypothesis is supported by studies of two groups of persons known to have low catecholamine levels: persons subjected to prolonged bedrest and persons with syndromes characterized by low circulating catecholamines (Bradbury-Eggleston syndrome and dopamine beta-hydroxylase deficiency). Both groups exhibit the symptoms mentioned. The increasing evidence that autonomic mechanisms underlie many of the physiologic consequences of weightlessness suggests that new pharmacologic approaches (such as administration of beta-blockers and/or sympathomimetic amines) based on these findings may attenuate these unwanted effects.

Effect of simulated microgravity on cardiopulmonary baroreflex control of forearm vascular resistance.

The stimulus-response characteristics of cardiopulmonary baroreflex control of forearm vascular resistance (FVR) were studied in 11 healthy men before and after 7 days of 6 degrees head-down bedrest to test the hypothesis that microgravity alters this reflex response. We assessed the relationship between stimulus [changes in central venous pressure (delta CVP)] and reflex response (delta FVR) during unloading of cardiopulmonary baroreceptors with lower body negative pressure (LBNP; 0 to -20 mmHg). delta CVP during bedrest and LBNP was estimated from peripheral vein pressures in the dependent right arm. Compared with prebedrest baseline, plasma volume and estimated CVP were decreased by 13 and 33%, respectively, at 7 days of bedrest. Progressive reflex forearm vasoconstriction occurred in response to graded reductions in estimated CVP during LBNP, and delta FVR per unit delta CVP was doubled after bedrest. The increase in sensitivity of the cardiopulmonary baroreflex control of FVR was related to reduced circulating blood volume, suggesting that enhanced peripheral vasoconstriction in individuals adapted to microgravity can be attributed, in part, to hypovolemia. In addition, microgravity appears to alter the stimulus for cardiopulmonary baroreceptors to a lower operational range of CVP, suggesting the possibility of chronic resetting.

Altered baroreflex control of forearm vascular resistance during simulated microgravity.

Reflex peripheral vasoconstriction induced by activation of cardiopulmonary baroreceptors in response to reduced central venous pressure (CVP) is a basic mechanism for elevating systemic vascular resistance and defending arterial blood pressure during orthostatically-induced reductions in cardiac filling and output. The sensitivity of the cardiopulmonary baroreflex response [defined as the slope of the relationship between changes in forearm vascular resistance (FVR) and CVP] and the resultant vasoconstriction are closely and inversely associated with the amount of circulating blood volume. Thus, a high-gain FVR response will be elicited by a hypovolemic state. Exposure to microgravity during spaceflight results in reduced plasma volume. It is therefore reasonable to expect that the FVR response to cardiopulmonary baroreceptor unloading would be accentuated following adaptation to microgravity. Such data could provide better insight about the physiological mechanisms underlying alterations in blood pressure control following spaceflight. We therefore exposed eleven men to 6 degrees head-down bedrest for 7 days and measured specific hemodynamic responses to low levels of the lower body negative pressure to determine if there are alterations in cardiopulmonary baroreceptor stimulus-FVR reflex response relationship during prolonged exposure to an analog of microgravity.

Advantages and disadvantages of fludrocortisone or saline load in preventing post-spaceflight orthostatic hypotension.

The purpose of this study was to compare the effectiveness of saline load to fludrocortisone (florinef) as countermeasures for reduced plasma volume and orthostatic intolerance after spaceflight. Eleven males (ages 30-50 yr) underwent a 3-day ambulatory baseline period followed by 7 days of 6 degrees head-down bedrest, during which cardiopulmonary and arterial baroreflex sensitivity and plasma volume (PV) were determined. During pre-bedrest and 2.5 h after treatment on day 8, PV was also measured and subjects underwent a 15-min unsupported stand test. Treatments consisted of 8 salt tablets (1 g NaCl per tablet) and 960 ml of water in 5 subjects and 0.6 mg (0.2 mg x 3) over 24 h in the other 6 subjects. PV decreased by 12% on day 7 of bedrest. This was restored on day 8 by florinef but not by saline load. The effect of florinef on PV was paralleled by decreases in urine volume and the urinary sodium/potassium ratio. Reduced PV was associated with greater vascular resistance for the same drop in central venous pressure, suggesting less vasoconstriction reserve after bedrest. Carotid baroreflex control of heart rate was attenuated after 7 days of bedrest. Both baroreflex functions were restored by florinef but not saline load. Only 1 of 6 subjects showed syncopal symptoms in the florinef-treated group, whereas 4 of 5 subjects did so in the saline-load group. Acute florinef treatment appears to have distinct advantages as a protective measure for post-bedrest orthostatic intolerance, not only through its salt retaining, volume-expanding mineralcorticoid effect, but possibly through its actions on baroreflex and sympathetic functions.

Gender differences in endocrine responses to posture and 7 days of -6 degrees head-down bed rest.

Endocrine regulation of fluids and electrolytes during 7 days of -6 degrees head-down bed rest (HDBR) was compared in male (n = 8) and, for the first time, female (n = 8) volunteers. The subjects' responses to quiet standing for 2 h before and after HDBR were also tested. In both sexes, diuresis and natriuresis were evident during the first 2-3 days of HDBR, resulting in a marked increase in the urinary Na(+)-to-K+ ratio and significant Na+ retention on re-ambulation. After the 1st day of HDBR, plasma renin activity (PRA) was increased relative to aldosterone (Aldo), plasma volume was decreased, and the renal response to Aldo appeared to be appropriate. Circulating levels of arginine vasopressin, cortisol, and ACTH were unchanged during HDBR. Plasma testosterone decreased slightly on day 2 of HDBR in males. The ratio of early morning ACTH to cortisol was lower in females than in males because ACTH was lower in females. Urinary cortisol increased and remained elevated throughout the HDBR in males only. There were no gender differences in the responses to 7 days of HDBR, except those in the pituitary-adrenal system; those differences appeared unrelated to the postural change. The provocative cardiovascular test of quiet standing before and after HDBR revealed both sex differences and effects of HDBR. There were significant sex differences in cardiovascular responses to standing before and after HDBR. Females had greater PRA and Aldo responses to standing before HDBR and larger Aldo responses to standing after HDBR than males.(ABSTRACT TRUNCATED AT 250 WORDS)