Current Pharmaceutical Biotechnology - Volume 6, Issue 4, 2005

Human exploration of space raises plenty of questions regarding physiological changes within the body subjected to a new and foreign environment. Nearly every component of the human body is affected. During microgravity conditions, the almost complete reduction in weight of all its components, plus exposure to heightened levels and different types of radiation may work together to increase risk during space travel. Still, the difference between 'Spaceflight' and 'Earthbound' Medicine is not as big as it looks. The basic biological principles are the same, no matter what particular condition of travel we are subjected to. And travel it is: We are on a galactic journey, eternally in motion. Earth is nothing less than a great spaceship, complete with a functioning and stable life support system (the only reliably functioning one we know of) that, incidentally, we might be in the process of jeopardizing right now. Human space exploration is important for several reasons, one being that it works as an eye-opener, showing our home planet from above and demonstrating its beauty and fragility. At the end, this might be more important than hundreds of 'spin-offs' from spaceflight research and development. Psychological effects (confinement, isolation, boredom, lack of leisure perspectives, etc); effects of radiation; and effects of changed gravitational environment (microgravity during ballistic phases, hyper-G during launches, aerobraking or landing) are the main problem drivers of human space flight. Humans have proven they can spend long time periods in space without obvious biomedical complications (up to 14 months as current world record: Valery V. Polyakov, M.D.). However, extended duration flights, as human missions to Mars, will pose bigger difficulties: Higher radiation dose, increased feeling of isolation and no immediate return option, longer absence of Earth-like gravitational pull, with possible aggravation of deconditioning phenomena. While the latter point could be resolved using artificial gravity, there is no way to avoid solar and cosmic radiation (with the exception of shortterm stay in 'safe havens') and to reliably counter potential psychological complications. However, compared with a multitude of occupational high-risk environments, it seems that human travel to Mars does not constitute an unusually high jeopardy to crew health and performance. From a medical point of view, adaptation capabilities seem sufficient to deal with foreseeable challenges of such an endeavor. It is important to understand that gravity governs the organization and function of all life in the biosphere. Organisms are continuously under gravitational influence, which shapes their anatomy and physiology. The biological consequences and implications of long-term alteration of our gravitational environment are unknown. Human exploration of the Moon, Mars, and other destinations in our solar system will stimulate scientific breakthroughs and spawn new medical paradigms. This intellectual 'spin-off' will prove to be amongst those things that last in history.

We used various orthostatic stimulus combinations to better understand the physiology and countermeasure potential of repeated change of body position in humans. The purpose of the investigations reported was threefold: To investigate cardiovascular and hormonal effects of repeated transition between partially antiorthostatic (-30° HDT) and partially head-up passive body tilt (+30° HUT). Protocol Y denotes the repeated transition between these two body positions; To apply, in the same test persons, repeated transition between supine and passive upright (Protocol X), and to compare the effect of the two protocols; To find out which stimulus pattern provides the largest physiological effects and, hence, presumably the largest countermeasure potential. We chose our tilt protocol according to tilt angle sine ranges: The sine difference is 1.0 both in Protocol X (sine=0 vs. sine=1.0) and Y (sine=-0.5 vs. sine=+0.5) since this difference, and not the angle change per se, determines hydrostatic effect intensities. Due to longer-lasting neurohormonal effects elicited by tilting procedures, they all should be a useful countermeasure against post-immobilization orthostatic instability, a conjecture not yet been tested in this specific form. Therefore, one of the questions asked in this study were if movement between the two defined body positions produces similar changes when employing Protocol X vs. Protocol Y.

This review summarizes what has been learned from studies of human neurovestibular system in weightless conditions, including balance and locomotion, gaze control, vestibular-autonomic function and spatial orientation, and gives some examples of the potential Earth benefits of this research. Results show that when astronauts and cosmonauts return from space flight both the peripheral and central neural processes are physiologically and functionally altered. There are clear distinctions between the virtually immediate adaptive compensations to weightlessness and those that require longer periods of time to adapt. However, little is known to date about the adaptation of sensory-motor functions to long-duration space missions in weightlessness and to the transitions between various reduced gravitational levels, such as on the Moon and Mars. Results from neurovestibular research in space have substantially enhanced our understanding of the mechanisms and characteristics of postural, gaze, and spatial orientation deficits, analogous to clinical cases of labyrinthine- defective function. Also, space neurosciences research has participated in the development and application of significant new technologies, such as video recording and processing of three-dimensional eye movements and posture, hardware for the unencumbered measurement of head and body movement, and procedures for investigating otolith function on Earth. In particular, devices such as centrifugation or off-vertical axis rotation could enhance clinical neurological testing because it provides linear acceleration which specifically stimulates the otolith organs in a frequency range close to natural head and body movement.

Cardiovascular adaptations driven by exposure to weightlessness cause some astronauts to experience orthostatic intolerance upon return to Earth. Maladaptations of spaceflight that lead to hemodynamic instability are temporary, and therefore astronauts provide for researchers a powerful model to study cardiovascular dysfunction in terrestrial patients. Orthostatic intolerance in astronauts is linked to changes in the autonomic control of cardiovascular function, and so patients that suffer neurocardiogenic syncope may benefit from a greater understanding of the effects of spaceflight on the autonomic nervous system. In addition, appropriate autonomic compensation is fundamental to the maintenance of stable arterial pressures and brain blood flow in patients suffering traumatic bleeding injuries. The application of lower body negative pressure (LBNP), an experimental procedure used widely in aerospace physiology, induces autonomic and hemodynamic responses that are similar to actual hemorrhage and therefore may emerge as a useful experimental tool to simulate hemorrhage in humans. Observations that standing astronauts and severely injured patients are challenged to maintain venous return has contributed to the development of an inspiratory impedance threshold device that serves as a controlled "Mueller maneuver" and has the potential to reduce orthostatic intolerance in returning astronauts and slow the progression to hemorrhagic shock in bleeding patients. In this review, we focus on describing new concepts that have arisen from studies of astronauts, patients, and victims of trauma, and highlight the necessity of developing the capability of monitoring medical information continuously and remotely. Remote medical monitoring will be essential for longduration space missions and has the potential to save lives on the battlefield and in the civilian sector.

The present manuscript summarizes recent discoveries that were made by studying salt and fluid homeostasis in weightlessness. These data indicate that 1. atrial natriuretic peptide appears not to play an important role in natriuresis in physiology, 2. the distribution of body fluids appears to be tightly coupled with hunger and thirst regulation, 3. intrathoracic pressure may be an important co-regulator of body fluid homeostasis, 4. a so far unknown low-affinity, high capacity osmotically inactive sodium storage mechanism appears to be present in humans that is acting through sodium/hydrogen exchange on glycosaminoglycans and might explain the pathophysiology, e.g., of salt sensitive hypertension. The surprising and unexpected data underline that weightlessness is an excellent tool to investigate the physiology of our human body: If we knew it, we should be able to predict changes that occur when gravity is absent. But, as data from space demonstrate, we do not.

The detrimental impact of long duration space flight on physiological systems necessitates the development of exercise countermeasures to protect work capabilities in gravity fields of Earth, Moon and Mars. The respective rates of physiological deconditioning for different organ systems during space flight has been described as a result of data collected during and after missions on the Space Shuttle, International Space Station, Mir, and bed rest studies on Earth. An integrated countermeasure that simulates the body's hydrostatic pressure gradient, provides mechanical stress to the bones and muscles, and stimulates the neurovestibular system may be critical for maintaining health and well being of crew during long-duration space travel, such as a mission to Mars. Here we review the results of our studies to date of an integrated exercise countermeasure for space flight, lower body negative pressure (LBNP) treadmill exercise, and potential benefits of its application to athletic training on Earth. Additionally, we review the benefits of Lower Body Positive Pressure (LBPP) exercise for rehabilitation of postoperative patients. Presented first are preliminary data from a 30-day bed rest study evaluating the efficacy of LBNP exercise as an integrated exercise countermeasure for the deconditioning effects of microgravity. Next, we review upright LBNP exercise as a training modality for athletes by evaluating effects on the cardiovascular system and gait mechanics. Finally, LBPP exercise as a rehabilitation device is examined with reference to gait mechanics and safety in two groups of postoperative patients.

Autonomic neural functions are important to regulate vital functions in the living body. There are different methods to evaluate indirectly and directly autonomic, sympathetic and parasympathetic, neural functions of human body. Among various methods, microneurography is a technique to evaluate directly sympathetic neural functions in humans. Using this technique sympathetic neural traffic leading to skeletal muscles (muscle sympathetic nerve activity; MSNA) can be recorded from human peripheral nerves in situ. MSNA plays essentially important roles to maintain blood pressure homeostasis against gravity. Orthostatic intolerance is an important problem as an autonomic dysfunction encountered after exposure of human beings to microgravity. There exist at least two different types of sympathetic neural responses, low and high responders to orthostatic stress in orthostatic hypotension seen in neurological disorders. To answer the question if post-spaceflight orthostatic intolernace is induced by low or high MSNA responses to orthostatic stress, MSNA was microneurographically recorded for the first time before, during and after spaceflight in 1998 under Neurolab international research project. The same activity has been recorded during and/or after ground-based short- and long-term simulations of microgravity. MSNA was rather enhanced on the 12th and 13th day of spaceflight and just after landing day. Postflight MSNA response to head-up tilt was well preserved in astronauts who were orthostatically well tolerant. MSNA was suppressed during short-term simulation of microgravity less than 2 hours but was enhanced after long-term simulation of microgravity more than 3 days. Orthostatic intolerance after exposure to long-term simulation of microgravity was associated with reduced MSNA response to orthostatic stress with impaired baroreflex functions. These findings obtained from MSNA recordings in subjects exposed to space as well as short- and long-term simulations of microgravity indicate that sympathetic neural control is lowered when exposed to short-term microgravity but becomes enhanced after exposure to long-tem micrograivity. A lack of enhanced sympathetic neural response to orhtostatic stress may induce orthostatic intolerance. Based on these findings effective countermeasures should be developed to prevent autonomic dysfunctions induced by exposure to microgravity. These include development of prescription and devices of physical exercise, electrical and magnetic nerve stimulations, body vibration, elastic bandage and stocking, lower body negative pressure, artificial gravity, medical drugs, and combinations of them. These countermeaures will be beneficial to prevent autonomic dysfunctions related to gravitational stress such encountered in bedridden subjects as orthostatic hypotension, atrophy of antigravity muscles and so on. This is particularly important in the present aged-society with many bedridden elderly people. The knowledge accumulated from studies on autonomic neural functions in space should be very useful to establish effective countermeasures and preventive methods for gravity-dependent autonomic dysfunctions.

The human cardiovascular system and regulation of fluid volume are heavily influenced by gravity. When decreasing the effects of gravity in humans such as by anti-orthostatic posture changes or immersion into water, venous return is increased by some 25%. This leads to central blood volume expansion, which is accompanied by an increase in renal excretion rates of water and sodium. The mechanisms for the changes in renal excretory rates include a complex interaction of cardiovascular reflexes, neuroendocrine variables, and physical factors. Weightlessness is unique to obtain more information on this complex interaction, because it is the only way to completely abolish the effects of gravity over longer periods. Results from space have been unexpected, because astronauts exhibit a fluid and sodium retaining state with activation of the sympathetic nervous system, which subjects during simulations by head-down bed rest do not. Therefore, the concept as to how weightlesness affects the cardiovascular system and modulates regulation of body fluids should be revised and new simulation models developed. Knowledge as to how gravity and weightlessness modulate integrated fluid volume control is of importance for understanding pathophysiology of heart failure, where gravity plays a strong role in fluid and sodium retention.

Echocardiographic measurements of astronaut cardiac function have documented an initial increase, followed by a progressive reduction in both left ventricular end-diastolic volume index and stroke volume with entry into microgravity (μ-G). The investigators hypothesize that the observed reduction in cardiac filling may, in part, be due to the absence of a gravitational acceleration dependent, intraventricular hydrostatic pressure difference in μ-G that exists in the ventricle in normal gravity (1-G) due to its size and anatomic orientation. This accelerationdependent pressure difference, ΔPLV, between the base and the apex of the heart for the upright posture can be estimated to be 6660 dynes/cm2 (≈5 mm Hg) on Earth. ΔPLV promotes cardiac diastolic filling on Earth, but is absent in μ-G. If the proposed hypothesis is correct, cardiac pumping performance would be diminished in μ-G. To test this hypothesis, ventricular function experiments were conducted in the 1-G environment using an artificial ventricle pumping on a mock circulation system with the longitudinal axis anatomically oriented for the upright posture at 45° to the horizon. Additional measurements were made with the ventricle horizontally oriented to null ΔPLV along the apex-base axis of the heart as would be the case for the supine posture, but resulting in a lesser hydrostatic pressure difference along the minor (anterior-posterior) axis. Comparative experiments were also conducted in the μ-G environment of orbital space flight on board the Space Shuttle. This paper reviews the use of an automated cardiovascular simulator flown on STS-85 and STS-95 as a Get Away Special payload to test this hypothesis. The simulator consisted of a pneumatically actuated, artificial ventricle connected to a closed-loop, fluid circuit with adjustable compliance and resistance elements to create physiologic pressure and flow conditions. Ventricular instrumentation included pressure transducers in the apex and base as well as immediately upstream of the inflow valve and downstream of the outflow valve, and a flow probe downstream of the outflow valve. By varying the circulating fluid volume, ventricular function could be determined for varying preload pressures at a regulated, mean afterload pressure of 95 mm Hg. This variation in preload condition permitted the construction of a ventricular function curve for the μ-G environment for comparison to the same curve for the 1-G environment. Data were collected from both missions at the upper end of the ventricular function curve. Experiment operation in the 1-G, supine orientation or in the μ-G environment eliminated the ΔPLV observed in the 1-G, upright orientation. Consistent with the hypothesis, additional atrial pressure was required in μ-G to obtain stroke volumes and flow rates similar to those measured in 1-G for the upright posture. The necessary increase in atrial pressure was approximately 5 mm Hg in these experiments. In the same range of flow rates and stroke volumes, similar flows were observed in the 1-G supine posture for atrial pressures intermediate to the 1-G upright and μ-G values, also consistent with the hypothesis. Additional experiments on board the Space Shuttle are in preparation to gather data across the rest of the normal physiologic range of the ventricular function curve.

Exposure to space flight conditions has been shown to result in alterations in immune responses. Changes in immune responses of humans and experimental animals have been shown to be altered during and after space flight of humans and experimental animals or cell cultures of lymphoid cells. Exposure of subjects to ground-based models of space flight conditions, such as hindlimb unloading of rodents or chronic bed rest of humans, has also resulted in changes in the immune system. The relationship of these changes to compromised resistance to infection or tumors in space flight has not been fully established, but results from model systems suggest that alterations in the immune system that occur in space flight conditions may be related to decreases in resistance to infection. The establishment of such a relationship could lead to the development of countermeasures that could prevent or ameliorate any compromises in resistance to infection resulting from exposure to space flight conditions. An understanding of the mechanisms of space flight conditions effects on the immune response and development of countermeasures to prevent them could contribute to the development of treatments for compromised immunity on earth.