GBT1118, a potent allosteric modifier of hemoglobin O-2 affinity, increases tolerance to severe hypoxia in mice

Abstract

Adaptation to hypoxia requires compensatory mechanisms that affect O-2 transport and utilization. Decreased hemoglobin (Hb) O-2 affinity is considered part of the physiological adaptive process to chronic hypoxia. However, this study explores the hypothesis that increased Hb O-2 affinity can complement acute physiological responses to hypoxia by increasing O-2 uptake and delivery compared with normal Hb O-2 affinity during acute severe hypoxia. To test this hypothesis, Hb O-2 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 O-2 affinity and decreased the P-O2 at which 50% of Hb is saturated with O-2 (P-50) 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-2 saturation by 16% (70 mg/kg) and 40% (140 mg/kg) relative to the control group during 5% O-2 hypoxia. In addition, a GBT1118-induced increase in Hb O-2 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-2 saturation and improved blood flow in GBT1118-treated groups preserved higher interstitial tissue P-O2 than in the control group during 5% O-2 hypoxia. In conclusion, increased Hb O-2 affinity enhanced physiological tolerance to hypoxia, as evidenced by improved hemodynamics and tissue oxygenation. Therefore, pharmacologically induced increases in Hb O-2 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 O-2 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.