Historically, animal investigations have preceded human explorations into space (55), and space physiologists have developed animal models to predict human responses. Although the Goldberg Report (16) makes a compelling argument that animal investigations in a microgravity environment should be considered as a national scientific priority, human safety concerns, funding availability, study section priority scores, and spacecraft constraints have essentially directed animal research in space toward understanding the adaptive responses of humans.
Although it is convenient to list the beginning of the life science space age with the orbital flight of Gagarin on April 12, 1961 and the sub-orbital flight of Shepard on May 5, 1961 (37), these historic events occurred only after extensive studies had been conducted between 1946 and 1961 using rockets, satellites, and capsules containing mice, rats, dogs, chimpanzees, and assorted invertebrates. However, it was in 1960 that vertebrates (dogs, rats, mice) were successfully recovered from an orbital flight in microgravity (41).
In the early stages of the space programs conducted by either the Russians or Americans, the primary purposes of the animal models were to: a) define the biological limits, b) establish safety standards, c) determine radiation hazards, d) perfect life-support systems, and d) to characterize physiological responses and to identify the responsible mechanisms. With the completion of successful missions and the analysis of their experiments, the relative importance of these purposes for animal experimentation has changed so that more emphasis is focused on physiological responses, mechanisms, and countermeasures and less on biological limits and radiation hazards(22,37,41).
Even though the number of species that have flown in space has increased markedly since 1960 (Table 1), it is important to realize that no Russian or American animal microgravity experiment designed to elucidate human responses, mechanisms, or countermeasures has been conducted longer than 22.5 d (22). Because rodents have a short life span and will be utilized in future space flights, there is a tendency for some in the space community to assume that microgravity changes in biological functions will be modified by an aging factor of 20-25. However, extrapolation proponents of short-term animal data need to be restrained from following this logic and reminded that the longevity of a rodent erythrocyte is similar to what is reported for humans-100-120 d. Consequently, the current physiological database from flight animals is only relevant for predictive and countermeasure purposes, for short-duration experiments and long-duration animal flights are desperately needed.
ANIMALS AND SIMULATED MICROGRAVITY EXPERIMENTS
For humans, the horizontal bed rest or the 6° head-down tilt (HDT) while in bed have been widely accepted as appropriate models for humans to simulate microgravity conditions for most anatomical and physiological systems(35), the exception being the structure and function of the lung (50). Moreover, the Russians have conducted select HDT experiments that have lasted from 7 to 366 d(32). With animals, there are several simulated microgravity models currently in use (Morey et al. (33), Musacchia et al. (34), Overton and Tipton(39), and the Stump-Tipton one-leg model(47), which exhibit anatomical and physiological changes that are consistent with the fluid shift, loss of sensory stimuli, or mechanical deprivation theories to explain microgravity changes in humans and animals (26,36). All models incorporate the head-down position, the hindlegs being non-weightbearing, and the animal being suspended by either the tail, webbing, or custom-made harness.
Of these animal models, the Morey appears to be utilized by most investigators throughout the world and the Stump-Tipton model has the greatest promise of differentiating the physiological effects of bone-muscle weight support from non-weight support in the same animal. As shown inFigure 1, hindlegs that were weightbearing during a 14-d HDT rat experiment had soleus muscles that did not atrophy when compared with soleus muscles removed from hindlimbs that were suspended and non-weightbearing. Although not shown in Figure 1, soleus muscle citrate synthase activity in either the weight supporting or non-weight supporting leg was significantly lower than in the control animals. This result indicated the weight support stimulus (approximately 20% of the body weight) was adequate to maintain muscle mass but inadequate to prevent a loss in muscle aerobic activity (47). The significance of these animal results is that they support the mass changes noted for humans and animals in microgravity (25,47) and provide a rationale for vigorous countermeasures that increase muscle metabolic activity.
Although several HDT experiments with humans have lasted a year or more, this has not been the situation with simulated microgravity studies with animals. Specifically, Elder and McComas (12) conducted a 240-d HDT study with rats that started when the animals were 21 d old, and Zhang et al. (62) performed several suspension investigations that lasted between 90 and 120 d. Of the investigators, only the latter was concerned with cardiovascular changes.
RESTING HUMAN CARDIOPULMONARY RESULTS AND ANIMAL SIMULATED MICROGRAVITY STUDIES
For purposes of this section, the relevance of results from simulated animal experiments is discussed with regard to the functional models of Grigor'yev and Yegorov (18), and Nicogossian and coworkers (36) that have been proposed using results obtained from cosmonauts and astronauts.
Recently published pulmonary function results during SLS-1 indicated that diffusion capacity was increased with elevations in the membrane-diffusing component and in capillary volume (43). Other changes noted were reductions in total lung volume and vital capacity. Contrary to expectations, microgravity did not eliminate the inhomogeneities between ventilation and perfusion, indicating that these differences are independent of gravitational influences (43). To date, similar experiments have not been performed with animals flown in space, and there has been little interest in using the suspended model for this purpose, because of the belief that a head-down position in either humans or animals cannot simulate microgravity conditions (50).
Cardiac Mass and Contractility
Although Charles and Lathers (6) have indicated that exposure to microgravity (5 to 84 d) will be associated with decreases in cardiac volumes (≈15%) and calculated left ventricular mass (11%), this concept is not always included by Russian investigators in their models for long-term flights (18). However, findings from animals flown in space (17) or from those suspended 90 d or longer (20) indicate that cardiac mass will exhibit gross and ultrastructural changes that are consistent with the concept of cardiac atrophy. While there is some uncertainty whether cardiac contractility will diminish in humans with exposure to microgravity(7), the simulated microgravity data of Zhang(61) from rats convincingly demonstrated that this was the case, although the responsible mechanisms were obscure. Future studies concerned with calcium release, ATPase sensitivity, and changes in the composition of cardiac myosin isoforms deserve consideration.
Fluid Shifts and Changes in Blood Volume
One of the most cited explanations for the physiological effects of microgravity is the fluid shift theory(18,24,26), which predicts cephalic fluid shifts with subsequent changes that include a decrease in plasma volume. Intrinsic with this theory are transcapillary fluid shifts between the microcirculation and the surrounding tissues as determined by hydrostatic and colloid osmotic pressures in accordance with the Starling equation(19,20). To date, hydrostatic or colloid osmotic pressures have not been measured in astronauts or cosmonauts. However, they have been evaluated in subjects participating in head-down tilt studies, and increases in capillary pressure, capillary flow, and tissue pressure have been demonstrated with decreases in plasma colloid pressure(19). When rats were suspended for several days, tissue pressures in the neck were increased and decreased in the hindlimbs(20).
Although features of the fluid shift theory have been challenged because of negative results (4,38), sufficient data have been obtained from astronauts and cosmonauts to indicate that plasma volume will be significantly reduced with space flight (7,24). Since the formation of red cells is also significantly decreased in microgravity (49), individuals return to Earth with marked decreases in blood volume. Although limited, post-flight data on primates indicated that reductions had occurred in blood and plasma volumes(1). After landing from a 9-d flight, reductions in red blood cell mass and in plasma volume/body mass ratios were reported for rats(54). The reduction in red cell mass was not associated with an increase in hemolysis, but with a decrease in the formation of erythrocytes. The authors concluded that the rat, like the human, appeared to“require a smaller blood volume in microgravity”(54). Since comparable changes have been reported in suspended rats (5), the HDT approach with rodents has considerable potential in investigating the responsible mechanisms that would include the influences of erythropoietin and testosterone.
Contrary to the predictions of the Henry-Gauer Hypothesis(34), and the results of the simulated microgravity human and animal experiments (14,45), direct measurements of right atrial pressure did not show an increase with conditions of 0 g (4). Consequently, ground-based investigations with animals are not recommended for explanations of the responsible mechanisms.
In-flight investigations during the 9-d SLS-1 study conducted by Prisk et al. (43) have shown that resting cardiac output and stroke volume will diminish when compared with ground-based measurements obtained in the supine position. Although comparative data are lacking in flight animals, resting cardiac output means in suspended rats increased markedly during the first 2 d of a 7-d HDT experiment, after which it decreased to a value lower than the pre-suspension mean(42). In the 7-d HDT study by Brizzee and Walker(5), they also found lower resting cardiac output values in their experimental animals. Since the decreases in cardiac output and stroke volume with microgravity could be explained, in part, by a reduction in myocardial contractility (61) and/or by a reduction in blood volume (5), the availability of an animal model provides an excellent opportunity for meaningful research on potential mechanisms and countermeasures.
Data summarized by Charles and Lathers (6) indicates in-flight resting heart rate will remain elevated in missions that last longer than 30 wk. Systolic blood pressure was also increased, but for a shorter period. Similar results have been noted with rats that have been suspended for 2 wk or longer (unpublished observation). Whether these changes can be attributed to the increased activity of the sympathetic nervous system is unclear, because measurements of in-flight plasma catecholamine concentrations exhibit decreases with short-term flights (23), and elevations with flights of several months (8). When measurements were made after landing, plasma concentrations of norepinephrine were lower than preflight values, while epinephrine values were elevated(24). Davydova et al. (9) measured norepinephrine during a 120-d HDT experiment and reported lower concentrations than baseline throughout the experiment. However, this was not the finding for epinephrine, as it was elevated on days 28 and 52. Kvetnyanski and colleagues(27) predicted that the number of myocardial beta receptors would increase in rats flown in space for 6.5 d. However, the opposite results occurred and they were uncertain whether this finding was unique to microgravity (27). With rat HDT investigations, plasma norepinephrine and epinephrine levels were significantly elevated above baseline for 7 d after suspension(60). During the next 7 d, norepinephrine remained elevated whereas epinephrine concentrations returned to within pre-suspension values (60). In a related study, Zhang et al.(62) reported that rats suspended for 90 d had no significant changes in the number or in the binding affinity of their myocardial beta receptors when compared with ground-based controls. On the other hand, they did report that the α1-adrenoreceptors of the suspended rats had been down-regulated (62). Additional simulated microgravity studies will be needed to confirm these latter results and to reconcile their differences with the reports of Kvetnyanski et al.(27).
Post-flight studies of short-term missions by Fritsch and associates(13) have demonstrated vagally mediated carotid baroreceptor-cardiac reflex responsiveness was decreased when compared with pre-flight results. Although there are no comparable in-flight or post-flight results from animals, two ground-based baroreceptor investigations with rats(5,62) indicated that the heart rate-blood pressure relationships and the operating point had been shifted in the suspended animals (62). Specifically, when compared with the caged control rats, the suspended group had an elevated minimum heart rate plateau and reduced operative range (62). However, if the baroreceptor response is measured when the animals are weightbearing, the significant differences between the two groups is lost(5). When rats were suspended for 90 d and subjected to conditions of lower-body negative pressure (61), they exhibited a greater decrease in mean blood pressure than their caged controls as the negative pressure increased, suggesting that suspension per se had impaired the regulatory functions of the carotid and aortic baroreceptors (61). These collective results also reinforce the value of using select ground-based animal studies to investigate human problems in space.
Preliminary in-flight results on limb blood flow in three astronauts(56) indicated that two had reductions of 30% or more of their pre-flight value, which was suggestive of peripheral vasoconstriction. This possibility was mentioned by Sulzman et al. (48) to explain the reduced ankle skin temperatures of two primates in space. When femoral blood flow (Doppler) was measured in HDT rats whose hindlimbs were either weight or non-weight supporting, the flow was significantly reduced in the leg that was suspended (47). McDonald and associates(29) measured resting blood flow in the soleus muscles of rats using radioactive microspheres while suspended or weightbearing and found no significant differences between the experimental and control rats. The same result occurred when the rats performed light-to-moderate exercise(29). However, using similar methodology, Woodman(58) and Woodman et al. (59) reported that weightbearing by suspended rats was associated with a significant reduction in the resting blood flow to these ankle extensors. Moreover, when these rats performed light and heavy exercise, soleus muscle blood flow of the suspended rats was significantly lower than the controls. Woodman et al. (59) explained their findings, in part, by a reduction in cardiac output and by a redistribution of flow because of increased vasoconstrictor activity of the sympathetic nervous system. While these studies indicate the need for additional investigations that are longer than 14 d, they indicate the importance of a “mechanical load” on skeletal muscles to maintain their mass and blood flow.
Reports by Levine and associates (28) and by Michel et al. (31) indicate that in-flight maximum oxygen consumption is maintained during flights lasting for 83 d. When attempts were made to measure arterialized capillary PO2 values of blood taken from the fingers of three cosmonauts who had been in microgravity between 83 and 178 d, the results were significantly lower than their pre-flight values(21). Although the authors felt this change was a reflection of a “disturbance” in the ventilation/perfusion ratio(21), this explanation has been minimized by West, as cited by Tipton (50) because their short-term in-flight results do not support such an impairment (43). However, in a review article by Kovalenko and Kasyan (26), they cite in-flight results from the lung, which indicated, on page 90,“oxygen tension decreased in tissues of cosmonauts from 56±2.0 to 30±3 mm Hg, while rate of oxygen consumption decreased in the tissues studied from 13 to 8.7 mm Hg/min.”
Although direct measurements of PO2 values have not been reported for either humans or animals in microgravity (50), they have been evaluated in humans participating in long-term simulated studies(46,53). Of interest were the two Russian reports that PO2 values during a 120-d head-down tilt were significantly reduced after 10 and 30 d, respectively (46,53). When arterial PO2 results were measured in suspended rats, significant decreases were noted after 1 d (51), which remained reduced during the 14-d period (Fig. 2). Although we felt this reduction in rats was associated with the presence of pulmonary edema, this hypothesis was not supported by measurement of wet and dry weights of the lung after 3 d of suspension ((20), unpublished observations). Whether space flight will cause shifts in resting metabolism and substrate utilization is unknown. Like primates flown in space(48), suspended rats have lower resting rectal temperatures than their caged controls (Fig. 3), which could reflect a decrease in metabolism and/or a reduction in blood flow to the periphery.
According to Macho (30), cosmonauts on flights lasting from 150 d to 326 d exhibited increases in plasma glucose, pyruvate, and lactate concentrations. These results were interpreted as demonstrating that glucose metabolism had been enhanced by the microgravity environment. Baldwin et al. (2) indicated from their post-flight results from animals flown in space that microgravity favors the utilization of carbohydrates by skeletal muscles. Moreover, investigations by Tischler et al. (52) with isolated skeletal muscles from flight and suspended rats showed they significantly increased their uptake of glucose when compared with findings from control animals. Although comparable flight data from animals are not available, suspended rats consistently demonstrate elevated resting lactate concentrations when compared with their caged controls (Table 2). The conclusion from these observations is the ground-based animal model shows promise in examining mechanistic features of space flight changes in resting metabolism and oxygen transport.
Because of the possibility of egress, exercise performance after return to Earth's gravity is an important consideration. When maximum performance tests have been conducted on astronauts after short-term flights, significant reductions have been reported for ˙VO2max, cardiac output, and stroke volume (28). Although relevant animal studies in space have not been performed, comparable human ground-based bed rest and head-down tilt investigations report similar findings(14,44). Rodent maximum oxygen consumption tests conducted by three different laboratories have convincingly demonstrated significant reductions in aerobic capacity of animals that have been suspended from 7 to 35 d (11,15,39,40). Moreover, cardiac output measurements on rats performing heavy exercise (75%˙VO2max) by Woodman (58) and Woodman et al.(59) showed the suspended group had significant reductions when compared with their caged controls (Fig. 4). This reduction was associated with a decrease in stroke volume and a reduction in the estimated sympathetic nerve traffic to the myocardium and periphery (58). When suspended rats perform maximal exercise, they exhibit increases in plasma concentrations of lactic acid and hydrogen ions (Table 2), a finding reported for humans participating in either bed rest or head-down tilt studies(44,57) and suggestive of an impaired oxygen supply and a shift toward carbohydrate metabolism.
Post-flight orthostatic intolerance by astronauts and cosmonauts continues to be a major consequence of returning to the surface of the Earth(3,36). Although there is no comparable evaluation for animals, the fact that suspended animals have reductions in blood volume(5), modifications in baroreceptor responsiveness(5,61), significant decreases in mean blood pressure with lower-body negative pressures (60), and less reactivity with the addition of norepinephrine to vascular rings(10), indicates it would be a useful model to investigate the responsible mechanisms. Recently, Blomqvist et al.(3) proposed that orthostatic intolerance was associated with an inability of the medullary cardiovascular center to effectively integrate the diverse information being received. However, for this intriguing hypothesis to be tested, animal investigations will be needed and the suspended model warrants consideration.
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