Although hypoxia tolerance in heterothermic mammals is well established, it is unclear whether the adaptive significance stems from hypoxia or other cellular challenge associated with euthermy, hibernation, or arousal. In the present study, blood gases, hemoglobin O 2 saturation (SO2), and indexes of cellular and physiological stress were measured during hibernation and euthermy and after arousal thermogenesis. Results show that arterial O 2 tension (PaO 2 ) and SO2 are severely diminished during arousal and that hypoxia-inducible factor (HIF)-1␣ accumulates in brain. Despite evidence of hypoxia, neither cellular nor oxidative stress, as indicated by inducible nitric oxide synthase (iNOS) levels and oxidative modification of biomolecules, was observed during late arousal from hibernation. Compared with rats, hibernating Arctic ground squirrels (Spermophilus parryii) are well oxygenated with no evidence of cellular stress, inflammatory response, neuronal pathology, or oxidative modification following the period of high metabolic demand necessary for arousal. In contrast, euthermic Arctic ground squirrels experience mild, chronic hypoxia with low SO 2 and accumulation of HIF-1␣ and iNOS and demonstrate the greatest degree of cellular stress in brain. These results suggest that Arctic ground squirrels experience and tolerate endogenous hypoxia during euthermy and arousal.torpor; ischemia; stroke; Spermophilus parryii; reperfusion; inflammation; oxidative stress HIBERNATION IS A UNIQUE PHYSIOLOGICAL STATE of prolonged periods of low body temperature, metabolism, blood flow, and other physiological processes that are disrupted by brief periodic arousal episodes when animals rewarm and reperfuse metabolically active tissues (7). During arousal thermogenesis, blood flow returns to brain and other organs in a reperfusionlike manner at a time of maximal oxygen demand (42, 58). Preservation of neuronal and other cellular morphology during low cerebral blood flow demonstrates that hibernating mammals tolerate pronounced fluctuations in blood flow (16,61). Physiological and cellular stress experienced during euthermy, hibernation, and arousal is less well characterized.Arterial oxygen tension (Pa O 2 ) and tissue lactate measurements show that hibernating ground squirrels are well oxygenated (16,20), sometimes exceeding values in the euthermic state (15). In contrast, oxygen supply may become limiting during arousal thermogenesis. Increases in brain tissue lactate levels during peak oxygen consumption during arousal from hibernation in bats suggest these animals experience oxygen deficiency during arousal and reperfusion (30). However, because tissue lactate was not reported for euthermic bats, it is unclear how brain tissue hypoxia experienced during arousal compares to the euthermic state. Moreover, Pa O 2 was not measured to address the relationship between blood and tissue oxygenation during euthermy, hibernation, and arousal. To characterize physiological challenges associated with arousal thermogenesis, we evaluated b...