Compared to Madison strain Sprague-Dawley rats, the Hilltop strain is resistant to acute hypoxic pulmonary vasoconstriction and pulmonary leak, a pathology resembling high altitude pulmonary edema (HAPE) in humans. Hypoxia inducible transcription factor-1 (HIF-1) mediates transcription of proteins that can "rescue" tissue from hypoxia, including vasoactive and angiogenic proteins such as inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF). Because these proteins have theoretical relevance to the etiology of HAPE, we hypothesized that hypoxia-resistant Hilltop rats acutely exposed to high altitude would have greater HIF-1 activity and expression of iNOS and VEGF as compared to hypoxia-sensitive Madison rats. Animals were exposed to normobaric normoxia or hypobaric hypoxia (18 h at 5486 m). The presence of nuclear HIF-1 heterodimer subunits, HIF-1-DNA binding, and iNOS and VEGF protein expression were determined in lung tissue. Hypoxic HIF-1beta expression, HIF-1-DNA binding, and iNOS and VEGF expression were greater in Hilltop than in Madison rats. After 18-h hypobaric hypoxia, HIF-1 activity and HIF-mediated protein expression were elevated in Hilltop rats, but not in Madison rats. To our knowledge, this is the first report of differing HIF-1 activation between two strains of animals with clearly divergent physiological responses to identical hypoxic conditions.