We Studied the in vivo persistence of hypoxia-inducible factor-l alpha (HIF-l alpha), main transducer of hypoxia, the differential response in organs exposed to the same degree of hypoxemia and the relationship with apoptosis. We measured HIF-l alpha (immunohistochemistry peroxidase and Western blot) and apoptosis (TUNEL) in heart, liver, kidney, gastrocnemius, and brain of rats exposed to chronic normobaric hypoxia (10% O-2) or normoxia (21% O-2) for 2 weeks. Despite same arterial O-2 pressure and increased hemoglobin concentration (219 +/- 5 vs. 124 +/- 4 g/L), the organs responded differently. While marked in brain, muscle, and kidney cortex, HIF-1 alpha Was undetectable in heart and liver. In kidney medulla, HIF-l alpha was high in both normoxia and hypoxia. By contrast, apoptosis was marked in heart, slight in kidney medulla, and undetectable in other organs. We conclude that the HIF-l alpha response to chronic hypoxia can be a Sustained phenomenon, but not in all organs, and that apoptosis responds differently from HIF-l alpha. (c) 2006 Elsevier Inc. All rights reserved.