The long term objective of this research is to improve our understanding of the mechanisms of adaptation to prolonged hypoxia, a condition which is a frequent feature of cardiopulmonary disease and which is also present in healthy individuals living at or sojourning to altitude for extended time periods. Hypoxia limits the delivery to and utilization of oxygen by the tissues, particularly in conditions of increased demand such as exercise, fever or other causes of increased metabolic activity. Hypoxia sets in motion several responses which appear to be directed to improve tissue oxygen supply: these include increased rate of red blood cell formation, increased ventilation, and changes in the oxygen affinity of hemoglobin. Although these features are well known, the underlying mechanisms, as well as their overall effectiveness in correcting the oxygen deprivation are poorly understood. The proposed studies will address two interrelated specific aims: 1. To study the mechanisms that limit maximal aerobic exercise capacity during acclimatization to hypoxia, in order to determine the role of changes in convective oxygen transport relative to other possible determinants of maximal oxygen uptake and 2. To determine the role of the sympathetic nervous system on the mechanisms of oxygen transport, uptake and utilization during exercise in prolonged hypoxia. These studies will be carried out in a rat model of acclimatization to hypoxia which has been in use in our laboratory for several years. This model allows a complete description of the oxygen transport system at rest and during hypoxic and normoxic exercise. The rat shares several features of acclimatization to hypoxia with humans, a fact that makes it an attractive animal model for these studies. The studies proposed will provide new information on the mechanisms of adaptation to prolonged hypoxia, and may increase our ability to manage conditions associated with oxygen deprivation.
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