The physiologic readjustment to chronic hypoxia (CHx) includes a temporary elevation of cerebral blood flow (CBF) for the initial 48 hours after which time CBF returns toward normoxic levels. This project seeks to determine the relation of the CBF response to the ventilatory acclimation (VA) response and to the development of acute mountain sickness (AMS) and high altitude cerebral edema (HACE). Our current studies using radiolabeled microspheres to measure regional CBF in conscious sheep have established that there are marked alterations in both the convective and the diffusive cerebral circulatory responses to O2 and CO2 following VA. The ratio of CBF to cerebral O2 consumption doubles early in CHx and intracranial pressure (Pic) increases. Cerebral venous hematocrit rises above arterial hematocrit indicating that a cerebral transcapillary fluid shift occurs. After 24 h of CHx, Pic declines in most sheep, probably due to a reduction of CSF volume. However, extraction of O2 by the brain declines progressively, reflecting both a hyperperfusion and a diffusion limitation. The latter response is probably due to HACE. The majority of sheep display signs which are indicative of AMS (decreased food intake, lethargy). In this project, we will obtain further experimental support for the hypotheses that cerebral vasodilation and elevation of brain microvascular pressure causes HACE and that AMS, in turn, is caused by a mild form of HACE. Microspheres will be used to measure CBF and isotope dilution methods will be used to estimate brain fluid shifts. We will test the fundamental hypothesis that CBF does not adapt to CHx per se. However, two physiologic modulators of the CBF response to CHx: the decline of PaCO2 induced by VA, and the elevation of blood O2 capacity, normally act to diminish hypoxic cerebral vasodilation and the potential for HACE and AMS. Currently, the etiologies of AMS and the lethal condition of HACE are considered to be unknown. Our studies should provide insights into the mechanisms which cause altitude illness and lead to a rational basis for prevention and treatment of these disorders. In addition, our results will be applicable to the illness associated with chronic lung disease.