Adaptation to hypoxia requires compensatory mechanisms that affect oxygen (O2) transport and utilization. Decreased hemoglobin (Hb)-O2 affinity is considered part of the physiological adaptive process to chronic hypoxia. This manuscript explores the hypothesis that increased Hb-O2 affinity can complement acute physiological responses to hypoxia by increasing O2 uptake and delivery when compared to normal Hb-O2 affinity during acute severe hypoxia. To test this hypothesis, mice Hb-O2 affinity was increased via oral administration of 70 or 140 mg/kg GBT1118. Systemic and microcirculatory hemodynamics and oxygenation parameters were studied during hypoxia in awake-instrumented mice. GBT1118 at 70 or 140 mg/kg increased Hb-O2 affinity and decreased the P50 (pO2 at which 50% of the Hb is saturated with O2) from 43 ± 1.1 to 18.3 ± 0.9, and to 7.7 ± 0.2 mmHg, respectively. In a dose-dependent fashion, GBT1118 increased arterial SO2 by 16% (70 mg/kg) and 40% (140 mg/kg) relative to the control during 5% O2 hypoxia. Additionally, GBT1118-induced increase in Hb-O2 affinity reduced the hypoxia-induced hypotension compared to the control. Moreover, microvascular blood flow was higher during hypoxia in the GBT1118 treated groups compared to the control group. The increased SO2 and improved blood flow in the GBT1118-groups preserved higher interstitial tissue pO2 compared to the control during 5% O2 hypoxia. In conclusion, increased Hb-O2 affinity enhanced physiological tolerance to hypoxia, as evidenced by improved hemodynamics and tissue oxygenation. Therefore, pharmacological increases in Hb-O2 affinity become a potential therapeutic approach to improve tissue oxygenation in pulmonary diseases characterized by severe hypoxemia.
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology