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.