GBT1118, a potent allosteric modifier of hemoglobin O₂ affinity, increases tolerance to severe hypoxia in mice

Adaptation to hypoxia requires compensatory mechanisms that affect O₂ transport and utilization. Decreased hemoglobin (Hb) O₂ affinity is considered part of the physiological adaptive process to chronic hypoxia. However, this study explores the hypothesis that increased Hb O₂ affinity can complement acute physiological responses to hypoxia by increasing O₂ uptake and delivery compared with normal Hb O₂ affinity during acute severe hypoxia. To test this hypothesis, Hb O₂ affinity in mice was increased by oral administration of 2-hydroxy-6-{[(2S)-1-(pyridine-3-carbonyl)piperidin-2yl] methoxy}benzaldehyde (GBT1118; 70 or 140 mg/kg). Systemic and microcirculatory hemodynamics and oxygenation parameters were studied during hypoxia in awake-instrumented mice. GBT1118 increased Hb O₂ affinity and decreased the Po₂ at which 50% of Hb is saturated with O₂ (P₅₀) from 43 ± 1.1 to 18.3 ± 0.9 mmHg (70 mg/kg) and 7.7 ± 0.2 mmHg (140 mg/kg). In a dose-dependent fashion, GBT1118 increased arterial O₂ saturation by 16% (70 mg/kg) and 40% (140 mg/kg) relative to the control group during 5% O₂ hypoxia. In addition, a GBT1118-induced increase in Hb O₂ affinity reduced hypoxia-induced hypotension compared with the control group. Moreover, microvascular blood flow was higher during hypoxia in GBT1118-treated groups than the control group. The increased O₂ saturation and improved blood flow in GBT1118-treated groups preserved higher interstitial tissue Po₂ than in the control group during 5% O₂ hypoxia. In conclusion, increased Hb O₂ affinity enhanced physiological tolerance to hypoxia, as evidenced by improved hemodynamics and tissue oxygenation. Therefore, pharmacologically induced increases in Hb O₂ affinity become a potential therapeutic approach to improve tissue oxygenation in pulmonary diseases characterized by severe hypoxemia.NEW & NOTEWORTHY This study establishes that pharmacological modification of hemoglobin O₂ affinity can be a promising and novel therapeutic strategy for the treatment of hypoxic hypoxia and paves the way for the clinical development of molecules that prevent hypoxemia.