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

Adaptation to hypoxia requires compensatory mechanisms that affect O transport and utilization. Decreased hemoglobin (Hb) O affinity is considered part of the physiological adaptive process to chronic hypoxia. However, this study explores the hypothesis that increased Hb O affinity can complement acute physiological responses to hypoxia by increasing O uptake and delivery compared with normal Hb O affinity during acute severe hypoxia. To test this hypothesis, Hb O affinity in mice was increased by oral administration of 2-hydroxy-6-{[(2)-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 O affinity and decreased the Po at which 50% of Hb is saturated with O (P) 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 O saturation by 16% (70 mg/kg) and 40% (140 mg/kg) relative to the control group during 5% O hypoxia. In addition, a GBT1118-induced increase in Hb O 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 O saturation and improved blood flow in GBT1118-treated groups preserved higher interstitial tissue Po than in the control group during 5% O hypoxia. In conclusion, increased Hb O affinity enhanced physiological tolerance to hypoxia, as evidenced by improved hemodynamics and tissue oxygenation. Therefore, pharmacologically induced increases in Hb O affinity become a potential therapeutic approach to improve tissue oxygenation in pulmonary diseases characterized by severe hypoxemia. This study establishes that pharmacological modification of hemoglobin O 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.